|
1
|
Yuan T, Edelmann D, Moreno V, Georgii E, de Andrade E Sousa LB, Pelin H, Jiang X, Kather JN, Tagscherer KE, Roth W, Bewerunge-Hudler M, Brobeil A, Kloor M, Bläker H, Brenner H, Hoffmeister M. Identification and external validation of tumor DNA methylation panel for the recurrence risk stratification of stage II colon cancer. Transl Oncol 2025; 57:102405. [PMID: 40311420 PMCID: PMC12088823 DOI: 10.1016/j.tranon.2025.102405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 03/19/2025] [Accepted: 04/25/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Tailoring surveillance and treatment strategies for stage II colon cancer (CC) after curative surgery remains challenging, and personalized approaches are lacking. We aimed to identify a gene methylation panel capable of stratifying high-risk stage II CC patients for recurrence beyond traditional clinical variables. METHODS Genome-wide tumor tissue DNA methylation data were analyzed from 562 stage II CC patients who underwent surgery in Germany (DACHS study). The cohort was divided into a training set (N = 395) and an internal validation set (N = 131), with external validation performed on 97 stage II CC patients from Spain. DNA methylation markers were primarily selected using the Elastic Net Cox model. The resulting prognostic index (PI), a combination of clinical factors and selected methylation markers, was compared to baseline models using clinical variables or microsatellite instability (MSI), with discrimination and prediction accuracy assessed through time-dependent receiver operating characteristic curves (AUC) and Brier scores. RESULTS The final PI incorporated age, sex, tumor stage, location, and 27 DNA methylation markers. The PI consistently outperformed the baseline model including age, sex, and tumor stage in time-dependent AUC across validation cohorts (e.g., 1-year AUC and 95 % confidence interval: internal validation set, PI: 0.66, baseline model: 0.52; external validation set, PI: 0.72, baseline model: 0.64). In internal validation, the PI also showed a consistently improved time-dependent AUC compared with a combination of MSI and tumor stage only. Nevertheless, the PI did not improve the prediction accuracy of CC recurrence compared to the baseline model. CONCLUSIONS This study identified 27 tumor tissue DNA methylation biomarkers that improved the discriminative power in classifying recurrence risk among stage II colon cancer patients. While this methylation panel alone lacks sufficient prediction accuracy for clinical application, its discriminative improvement suggests potential value as part of a multimodal risk-stratification tool.
Collapse
Affiliation(s)
- Tanwei Yuan
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Dominic Edelmann
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Víctor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO). Hospitalet de Llobregat, Barcelona, Spain; Colorectal Cancer Group, ONCOBELL, Bellvitge Biomedical Research Institute (IDIBELL). Hospitalet de Llobregat, Barcelona, Spain; Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona, Barcelona, Spain
| | | | | | | | - Xiaofeng Jiang
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
| | - Jakob Nikolas Kather
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
| | | | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Alexander Brobeil
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Matthias Kloor
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Leipzig Medical Center, Leipzig, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|
|
2
|
Delgado-Plasencia L, Boluda-Aparicio A, Marrero-Marrero P, Salido-Ruíz E, Torres-Monzón E, Peñalver-Alcaraz C, Phillbrick C, Jiménez-Sosa A. Impact of self-expandable metallic prosthesis on lymph node dissemination in obstructive left-sided colorectal cancer. Surg Endosc 2025; 39:3224-3235. [PMID: 40227483 PMCID: PMC12041179 DOI: 10.1007/s00464-025-11652-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/02/2025] [Indexed: 04/15/2025]
Abstract
BACKGROUND The introduction of self-expandable metal stent (SEMS) insertion in obstructive colorectal cancer (CRC) has been associated with an increased risk of tumor perforation, potentially leading to peritoneal dissemination, tumor cell spread via lymphatic vessels, perineural invasion, and peripheral bloodstream. The objective of this study was to assess the impact of SEMS placement on CRC lymph node metastasis. METHODS We retrospectively reviewed 48 patients with malignant colorectal obstruction treated with a temporary SEMS before elective surgery, and 51 patients with malignant colorectal obstruction who underwent elective surgery without prior SEMS placement. RESULTS No significant differences were found in the lymph node ratio (LNR) or in the results obtained from the logarithm of the ratio between positive and negative nodes (LODDS). Regarding recurrence, patients without SEMS had a fourfold higher risk of local recurrence compared to those with SEMS (19.6% vs. 6.3%), and a twofold higher risk of distant recurrence (31.4% vs. 14.6%). These differences were statistically significant for overall recurrence and for each local and distant recurrence individually (P = 0.02, P = 0.05, and P = 0.04, respectively). CONCLUSION SEMS placement in obstructive CRC not only shows the potential to suppress tumor growth, but also reduce nodal spread, as no differences in LNR and LODDS values were observed when comparing preoperative SEMS placement in patients with advanced left CRC.
Collapse
Affiliation(s)
- Luciano Delgado-Plasencia
- University of La Laguna, San Cristóbal de La Laguna, Spain.
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain.
| | - Antonio Boluda-Aparicio
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain
| | - Patricia Marrero-Marrero
- Department of General and Digestive Surgery, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain
| | - Eduardo Salido-Ruíz
- Department of Pathology, Hospital Universitario de Canarias. La Laguna, Tenerife, Spain
| | - Esther Torres-Monzón
- Nursing Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
| | | | - Caroline Phillbrick
- Department of Radiation Oncology, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
| | - Alejandro Jiménez-Sosa
- Department of Research Unit, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
| |
Collapse
|
|
3
|
Erdogan B, Usturalı Keskin FE, Özcan E, Küçükarda A, Güren AK, Köstek O, Hacioglu BM, Kodaz H. Assessment of new pathological markers in early stage colon cancer: Insights and limitations. World J Gastrointest Oncol 2025; 17:101325. [PMID: 40092924 PMCID: PMC11866233 DOI: 10.4251/wjgo.v17.i3.101325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/09/2024] [Accepted: 12/12/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND The decision to administer adjuvant chemotherapy to patients with local stage depends on specific high-risk features that are T4 tumor stage, presence of perineural invasion, lymphovascular invasion, poorly differentiated tumor histology, inadequate lymph node sampling (fewer than 12 lymph nodes), and evidence of tumor perforation or obstruction. Tumor-stroma ratio, tumor infiltrating lymphocytes (TIL), Crohn-like reaction (CLR), desmoid reaction, poorly differentiated clusters (PDC) are new pathological markers that are being studied. AIM To examine the relationship between new pathological markers and defined high risk factors, in early stage colorectal cancer. METHODS We evaluated 155 patients with the diagnosis stage I and II colorectal cancer between the years 2007 and 2021 who were treated at Trakya University Hospital, Department of Medical Oncology. We divided those with and without high-risk factors into two groups. We examined the relationship of new pathological markers with these groups and with pathological markers in risk factors. RESULTS There was no statistically significant correlation between presence of TIL, presence of PDC, presence of tumor budding, presence of CLR, presence of desmoid reaction and low and high-risk groups according to the degree of those with PDC (P = 0.82, P = 0.51, P = 0.77, P = 0.37, P = 0.83, respectively). In addition, no statistically significant correlation was found between the tumor-stroma ratio and low and high risk groups (P = 0.80). We found a statistically significant correlation between the presence of PDC and the presence of PDC grade 3 and T stage (P = 0.001, P = 0.001, respectively). It was determined that the presence of PDC and the frequency of grade 3 PDC increased with the advanced T stage. CONCLUSION No relationship was found between the presence of new pathological markers and high-low risk groups. When we examined the relationship between new and old pathological markers, only the frequency of detection of PDC and PDC grade 3 was found to be correlated with advanced T stage.
Collapse
Affiliation(s)
- Bulent Erdogan
- Department of Medical Oncology, Division of Medical Oncology, Department of Internal Medicine, Trakya University School of Medicine, Edirne 22000, Türkiye
| | | | - Erkan Özcan
- Division of Medical Oncology, Trakya University School of Medicine, Edirne 22000, Türkiye
| | - Ahmet Küçükarda
- Division of Medical Oncology, Department of Internal Medicine, Trakya University School of Medicine, Edirne 22000, Türkiye
| | - Ali Kaan Güren
- Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Marmara University, Istanbul 34000, Türkiye
| | - Osman Köstek
- Division of Medical Oncology, Department of Internal Medicine, Marmara University School of Medicine, Istanbul 34000, Türkiye
| | - Bekir Muhammet Hacioglu
- Division of Medical Oncology, Department of Internal Medicine, Trakya University School of Medicine, Edirne 22000, Türkiye
| | - Hilmi Kodaz
- Department of Medical Oncology, Acibadem Eskisehir Hospital, Eskisehir 26130, Türkiye
| |
Collapse
|
|
4
|
Klein J, Tran WT, Viswanathan S, Salgado R, Poortmans P, Machiels M. Tumour-infiltrating Lymphocytes and Radiation Therapy in Rectal Cancer: Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol) 2025; 39:103742. [PMID: 39854781 DOI: 10.1016/j.clon.2024.103742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 12/15/2024] [Accepted: 12/17/2024] [Indexed: 01/26/2025]
Abstract
AIM Tumour-infiltrating lymphocytes (TILs) represent a promising cancer biomarker. Different TILs, including CD8+, CD4+, CD3+, and FOXP3+, have been associated with clinical outcomes. However, data are lacking regarding the value of TILs for patients receiving radiation therapy (RT). We conducted a systemic review and meta-analysis of available data evaluating TILs for patients receiving curative-intent therapy including RT. MATERIALS AND METHODS Eligible studies presented a defined cohort of patients who all received curative-intent therapy, including RT, and also reported the relationship between any TIL score and either tumour response or survival outcomes. After comprehensive search of online databases (PubMed, EMBASE, Cochrane, and Web of Science), 2 authors conducted title, abstract, and whole-text review for quality and risk of bias following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Data from publications that met quality criteria were grouped via (1) TIL analysed, (2) pre- or post-RT TIL assessment, and (3) clinical outcome measured. RESULTS Initial search yielded 669 unique studies. Thirty-one studies met quality criteria, of which 20 studied rectal cancer (RC), 4 oesophageal, 3 pancreas, 2 lung, cervical/uterine 1 each. We conducted systematic review and meta-analysis of the RC publications. All except 2 were single-institutional cohort studies. After meta-analysis, the pre-RT epithelial CD8+ (p = 0.04) and stromal FOXP3+ (p = 0.01) counts were associated with survival without disease, while pre-RT epithelial (p = 0.02) and stromal (p = 0.001) FOXP3+ TILs were associated with overall survival. On post-RT analysis, epithelial (p = .04) and stromal (p = 0.02) CD8+ TILs were associated with survival without disease and epithelial CD8+ TILs were associated with overall survival (p = 0.01).Preoperative CD8+ and FOXP3+ TILs were generally associated with tumour response to RT, but meta-analysis was not conducted due to heterogeneity of response measurement techniques. CONCLUSION TILs represent a useful parameter for tumour response and survival outcomes for patients receiving curative-intent therapy, including RT for RC. Future work should aim to standardise TIL measurement and quantification methods and to develop protocols to clarify clinical application of these findings.
Collapse
Affiliation(s)
- J Klein
- Department of Radiation Oncology, State University of New York (SUNY) Downstate Health Sciences University, 450 Clarkson Ave, Brooklyn, NY, USA; Department of Radiation Oncology, Maimonides Medical Center, 6300 8th Ave, Brooklyn, NY, USA.
| | - W T Tran
- Department of Radiation Oncology, University of Toronto, 149 College St#504, Toronto, Ontario, Canada; Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, Ontario, Canada.
| | - S Viswanathan
- Department of Epidemiology and Population Health, Montefiore Einstein Comprehensive Cancer Center, 1300 Morris Park Ave, Block Building Room 315, Bronx, NY, USA.
| | - R Salgado
- Division of Research, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Australia; Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium.
| | - P Poortmans
- Faculty of Medicine and Health Sciences, University of Antwerp, Prinsstraat 13, 2000, Antwerp, Belgium; Department of Radiation Oncology, Iridium Netwerk, Oosterveldlaan 22, 2610, Antwerp, Belgium.
| | - M Machiels
- Faculty of Medicine and Health Sciences, University of Antwerp, Prinsstraat 13, 2000, Antwerp, Belgium; Department of Radiation Oncology, Iridium Netwerk, Oosterveldlaan 22, 2610, Antwerp, Belgium.
| |
Collapse
|
|
5
|
Ota G, Inoue R, Saito A, Kono Y, Kitayama J, Sata N, Horie H. Reduced Abundance of Phocaeicola in Mucosa-associated Microbiota Is Associated with Distal Colorectal Cancer Metastases Possibly through an Altered Local Immune Environment. J Anus Rectum Colon 2024; 8:235-245. [PMID: 39086872 PMCID: PMC11286368 DOI: 10.23922/jarc.2024-014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/17/2024] [Indexed: 08/02/2024] Open
Abstract
Objectives The aim of this study was to identify the microbiota whose decrease in tumor area was associated with the metastatic process of distal colorectal cancer (CRC). Methods Twenty-eight consecutive patients with distal CRC undergoing surgical resection in our hospital were enrolled. Microbiota in 28 specimens from surgically resected colorectal cancers were analyzed using 16S ribosomal ribonucleic acid gene amplicon sequencing and the relative abundance (RA) of microbiota was evaluated. The densities of tumor-infiltrating lymphocytes (TIL) and tumor associated macrophages (TAM) in the colorectal cancers were immunohistochemically evaluated. Results Phocaeicola was the most abundant microbiota in normal mucosa. The RA of Phocaeicola in tumor tissues tended to be lower than that in normal mucosa although the difference was not significant (p=0.0732). The RA of Phocaeicola at tumor sites did not correlate either with depth of tumor invasion (pT-stage) or tumor size, however they were significantly reduced in patients with nodal metastases (p<0.05) and those with distant metastases (p<0.001). The RA of Phocaeicola at tumor sites showed positive correlation with the densities of CD3(+) or CD8(+) TIL. Since P. vulgatus was the most dominant species (47%) of the Phocaeicola, the RA of P. vulgatus and CRC metastasis and its association with TIL and TAM were also investigated. P. vulgatus showed a similar trend to genus Phocaeicola but was not statistically significant. Conclusions A relative reduction of Phocaeicola attenuates the local anti-tumor immune response in distal CRC, which may facilitate metastatic spread.
Collapse
Affiliation(s)
- Gaku Ota
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Ryo Inoue
- Laboratory of Animal Science, Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, Hirakata, Japan
| | - Akira Saito
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yoshihiko Kono
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
- Clinical Research Center, Division of Translational Research, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hisanaga Horie
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
- Department of Operating Room Management, Jichi Medical University Hospital, Shimotsuke, Japan
| |
Collapse
|
|
6
|
Boldrini L, Chiloiro G, Cusumano D, Yadav P, Yu G, Romano A, Piras A, Votta C, Placidi L, Broggi S, Catucci F, Lenkowicz J, Indovina L, Bassetti MF, Yang Y, Fiorino C, Valentini V, Gambacorta MA. Radiomics-enhanced early regression index for predicting treatment response in rectal cancer: a multi-institutional 0.35 T MRI-guided radiotherapy study. LA RADIOLOGIA MEDICA 2024; 129:615-622. [PMID: 38512616 DOI: 10.1007/s11547-024-01761-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 01/03/2024] [Indexed: 03/23/2024]
Abstract
PURPOSE The accurate prediction of treatment response in locally advanced rectal cancer (LARC) patients undergoing MRI-guided radiotherapy (MRIgRT) is essential for optimising treatment strategies. This multi-institutional study aimed to investigate the potential of radiomics in enhancing the predictive power of a known radiobiological parameter (Early Regression Index, ERITCP) to evaluate treatment response in LARC patients treated with MRIgRT. METHODS Patients from three international sites were included and divided into training and validation sets. 0.35 T T2*/T1-weighted MR images were acquired during simulation and at each treatment fraction. The biologically effective dose (BED) conversion was used to account for different radiotherapy schemes: gross tumour volume was delineated on the MR images corresponding to specific BED levels and radiomic features were then extracted. Multiple logistic regression models were calculated, combining ERITCP with other radiomic features. The predictive performance of the different models was evaluated on both training and validation sets by calculating the receiver operating characteristic (ROC) curves. RESULTS A total of 91 patients was enrolled: 58 were used as training, 33 as validation. Overall, pCR was observed in 25 cases. The model showing the highest performance was obtained combining ERITCP at BED = 26 Gy with a radiomic feature (10th percentile of grey level histogram, 10GLH) calculated at BED = 40 Gy. The area under ROC curve (AUC) of this combined model was 0.98 for training set and 0.92 for validation set, significantly higher (p = 0.04) than the AUC value obtained using ERITCP alone (0.94 in training and 0.89 in validation set). CONCLUSION The integration of the radiomic analysis with ERITCP improves the pCR prediction in LARC patients, offering more precise predictive models to further personalise 0.35 T MRIgRT treatments of LARC patients.
Collapse
Affiliation(s)
- Luca Boldrini
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Giuditta Chiloiro
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | | | - Poonam Yadav
- Northwestern Memorial Hospital, Northwestern University Feinberg, Chicago, IL, USA
| | - Gao Yu
- Department of Radiological Sciences, University of California, Los Angeles, CA, USA
| | - Angela Romano
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Antonio Piras
- UO Radioterapia Oncologica, Villa Santa Teresa, Bagheria, Palermo, Italy
| | - Claudio Votta
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Lorenzo Placidi
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Sara Broggi
- Medical Physics, San Raffaele Scientific Institute, Milan, Italy
| | | | - Jacopo Lenkowicz
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Luca Indovina
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | - Michael F Bassetti
- Department of Human Oncology, School of Medicine and Public Heath, University of Wisconsin - Madison, Madison, USA
| | - Yingli Yang
- Department of Radiological Sciences, University of California, Los Angeles, CA, USA
| | - Claudio Fiorino
- Medical Physics, San Raffaele Scientific Institute, Milan, Italy
| | - Vincenzo Valentini
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy
| | | |
Collapse
|
|
7
|
Tao Y, Xie Y. Prognostic impact of CD4+ and CD8+ tumor-infiltrating lymphocytes in patients with colorectal cancer. Acta Chir Belg 2024; 124:35-40. [PMID: 36780176 DOI: 10.1080/00015458.2023.2180712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/12/2023] [Indexed: 02/25/2023]
Abstract
OBJECTIVE Tumor immune response has been suggested as an important indicator of cancer prognosis. This study was initiated to investigate the association between T lymphocytes and the prognosis of patients with colorectal cancer (CRC). METHODS Included in this study were 129 CRC patients who received surgical treatment in Henan Provincial People's Hospital from January 2003 to January 2014. The level of CD4+ and CD8+ T lymphocytes in tissues was detected by immunohistochemistry (IHC). Survival analysis was conducted by the Kaplan-Meier method and Cox proportional hazards model. RESULTS IHC staining showed that CD8+ T lymphocyte infiltration was high in 88 cases and low in 41 cases, while CD4+ T lymphocyte infiltration was high in 66 cases and low in 63 cases. The level of CD4+ and CD8+ T lymphocytes in CRC tissue was closely related to TNM stage and tumor invasion (p < 0.05). Follow-up analysis showed that both disease-free survival (DFS) and overall survival (OS) were better in patients with a high level of CD8+ and CD4 + CD8+ than those in patients with a low level (p < 0.05). Multivariate analysis showed that TNM stage, lymph node, CD8+ and CD4+ CD8+ were independent risk factors for DFS and OS (p < 0.05). CONCLUSION High level of CD8+ and CD4+ CD8+ may prove to be a potential predictor of better prognosis of CRC patients.
Collapse
Affiliation(s)
- Yong Tao
- Colorectal Surgery, Ningbo City First Hospital, Ningbo, China
| | - Ya Xie
- Colorectal Surgery, Henan Provincial People's Hospital, Zhengzhou, China
| |
Collapse
|
|
8
|
Zhong J, Xiong D, Liu Y, Yuan S. Association of antibiotic exposure with survival in patients with extensive-stage small cell lung cancer receiving immune checkpoint inhibitor therapy. Thorac Cancer 2024; 15:152-162. [PMID: 38010059 PMCID: PMC10788467 DOI: 10.1111/1759-7714.15172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/09/2023] [Accepted: 11/11/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have dramatically shifted the therapeutic paradigm of extensive-stage small cell lung cancer (ES-SCLC). Antibiotic (ATB) exposure before or during ICI therapy can harm the integrity of the gut microbiome and lead to intestinal dysbiosis, which has a profoundly negative impact on the treatment response for various malignancies. Whether this is applicable to ES-SCLC remains unclear. METHODS We retrospectively reviewed the electronic medical records of all patients diagnosed with ES-SCLC who were treated with ICI-based immunotherapies from July 2019 to December 2020 at Shandong Cancer Hospital and Institute, China. Outcomes with the use of ATBs before or after the first infusion of ICI, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analyses were also conducted using a Cox proportional hazards model. RESULTS A total of 214 patients were included, among whom 41 (19.2%) received ATBs within 2 months before or after the first initiation of ICI therapy and were assigned to the ATB group. The ATB group showed a shorter median PFS (4.3 vs. 6.3 months; HR = 1.43, 95% CI: 0.97-2.11; p = 0.043) and a significantly shorter median OS (6.9 vs. 13 months; HR = 1.47, 95% CI: 0.98-2.20; p = 0.033) than the non-ATB group. In the multivariate analysis, ATB exposure was markedly associated with worse PFS (HR = 1.47, 95% CI: 1.03-2.09, p = 0.035) and OS (HR = 1.46, 95% CI: 1.01-2.11, p = 0.043). CONCLUSIONS Our results demonstrate that ATB exposure was significantly associated with worse survival in ES-SCLC patients who received ICI therapy.
Collapse
Affiliation(s)
- Jiaqi Zhong
- Clinical Medical CollegeSouthwest Medical UniversityLuzhouChina
- Department of Radiation OncologyShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Dali Xiong
- Clinical Medical CollegeSouthwest Medical UniversityLuzhouChina
- Department of Radiation OncologyShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Yu Liu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University Digestive Endoscopy CenterJinanChina
| | - Shuanghu Yuan
- Clinical Medical CollegeSouthwest Medical UniversityLuzhouChina
- Department of Radiation OncologyShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesJinanChina
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| |
Collapse
|
|
9
|
Rocha Martins P, Luciano Pereira Morais K, de Lima Galdino NA, Jacauna A, Paula SOC, Magalhães WCS, Zuccherato LW, Campos LS, Salles PGO, Gollob KJ. Linking tumor immune infiltrate and systemic immune mediators to treatment response and prognosis in advanced cervical cancer. Sci Rep 2023; 13:22634. [PMID: 38114557 PMCID: PMC10730812 DOI: 10.1038/s41598-023-49441-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 12/08/2023] [Indexed: 12/21/2023] Open
Abstract
Cervical cancer (CC) poses a significant burden on individuals in developing regions, exhibiting heterogeneous responses to standard chemoradiation therapy, and contributing to substantial mortality rates. Unraveling host immune dynamics holds promise for innovative therapies and discovery of clinically relevant biomarkers. We studied prospectively locally advanced CC patients pre-treatment, stratifying them as responders (R) or non-responders (NR). R patients had increased tumor-infiltrating lymphocytes (TILs), while NR patients showed elevated PD-1 scores, CD8+ and PD-L2+ TILs, and PD-L1 immune reactivity. NR patients exhibited higher systemic soluble mediators correlating with TIL immune markers. R patients demonstrated functional polarization of CD4 T cells (Th1, Th2, Th17, and Treg), while CD8+ T cells and CD68+ macrophages predominated in the NR group. Receiver operating characteristic analysis identified potential CC response predictors, including PD-L1-immunoreactive (IR) area, PD-L2, CD8, FGF-basic, IL-7, IL-8, IL-12p40, IL-15, and TNF-alpha. Dysfunctional TILs and imbalanced immune mediators contribute to therapeutic insufficiency, shedding light on local and systemic immune interplay. Our study informs immunological signatures for treatment prediction and CC prognosis.
Collapse
Affiliation(s)
- Patrícia Rocha Martins
- Pathology Department, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
- Instituto Mário Penna, Belo Horizonte, MG, Brazil
| | - Kátia Luciano Pereira Morais
- Translational Immuno-Oncology Lab, Education and Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Center for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Nayane Alves de Lima Galdino
- Translational Immuno-Oncology Lab, Education and Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Center for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Adriana Jacauna
- Pathology Department, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Wagner C S Magalhães
- Instituto Mário Penna, Belo Horizonte, MG, Brazil
- CCATES - Centro Colaborador do SUS: Avaliação de Tecnologias e Excelencia em Saude, UFMG, Belo Horizonte, Brazil
- Pontificia Universidade Catolica de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana W Zuccherato
- Instituto Mário Penna, Belo Horizonte, MG, Brazil
- Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | | | | | - Kenneth J Gollob
- Instituto Mário Penna, Belo Horizonte, MG, Brazil.
- Translational Immuno-Oncology Lab, Education and Research Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
- Center for Research in Immuno-Oncology (CRIO), Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
- Center for Research in Immuno-Oncology (CRIO), Translational Immuno-Oncology Laboratory, Hospital Israelita Albert Einstein, Av. Albert Einstein, São Paulo, SP, 62705652-900, Brazil.
| |
Collapse
|
|
10
|
Zheng J, Zhang H, Li S, Kang Z, Zheng F, Yao Q, Zhang X, Wu Z, Wang J, Fang W, Li J, Chen G, Chen Y, Chen M. Prognostic value of Hematoxylin and eosin staining tumor-infiltrating lymphocytes (H&E-TILs) in patients with esophageal squamous cell carcinoma treated with chemoradiotherapy. BMC Cancer 2023; 23:1193. [PMID: 38053017 DOI: 10.1186/s12885-023-11684-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 11/27/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) by routine hematoxylin and eosin staining (H&E-TILs) are a robust prognostic biomarker in various cancers. However, the role of H&E-TILs in esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiotherapy (CCRT) has not been reported. The purpose of this study was to assess the prognostic value of H&E-TILs in ESCC treated with CCRT. METHODS The clinical data of 160 patients with ESCC treated with CCRT in our center between Jan. 2014 and Dec. 2021 were collected and retrospectively reviewed, and propensity score matching (PSM) analyses were performed. The H&E-TILs sections before CCRT were reassessed by two experienced pathologists independently. The H&E-TILs sections were classified into a positive group (+, > 10%) and a negative group (-, ≤ 10%) using 10% as the cutoff. The effects of H&E-TILs on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) were explored using the Kaplan‒Meier method, and the log-rank test was used to test the differences. Multivariable analysis was performed using the Cox proportion hazards model. RESULTS The short-term response to CCRT and the OS (P < 0.001), DMFS (P = 0.001), and LRFS (P < 0.001) rates were significantly different between the H&E-TILs (+) and H&E-TILs (-) groups. Subgroup analysis showed that H&E-TILs(+) with CR + PR group had a longer survival than H&E-TILs(-) with CR + PR, H&E-TILs(+) with SD + PD and H&E-TILs(-) with SD + PD group, respectively(P < 0.001). Furthermore, based on TCGA data, patients in the high TILs group had a better prognosis than those in the low TILs group. Multivariate analyses indicated that H&E-TILs and the short-term response to CCRT were the only two independent factors affecting OS, PFS, DMFS, and LRFS simultaneously, and H&E-TILs expression was associated with an even better prognosis for those patients with CR + PR. CONCLUSIONS H&E-TILs may be an effective and beneficial prognostic biomarker for ESCC patients treated with CCRT. Patients with H&E-TILs (+) with PR + CR would achieve excellent survival. Further prospective studies are required to validate the conclusions.
Collapse
Affiliation(s)
- Jifang Zheng
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Hejun Zhang
- Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Siya Li
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Zhaoxin Kang
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
- College of Computer and Data Science, Fuzhou University, Fuzhou, 350025, China
| | - Fei Zheng
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Qiwei Yao
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Xueqing Zhang
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Ziyi Wu
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Jiezhong Wang
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Weimin Fang
- Department of Thoracic Surgery Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Jiancheng Li
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Gang Chen
- Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Yuangui Chen
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Mingqiu Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
| |
Collapse
|
|
11
|
Zemanek T, Nova Z, Nicodemou A. Tumor-Infiltrating Lymphocytes and Adoptive Cell Therapy: State of the Art in Colorectal, Breast and Lung Cancer. Physiol Res 2023; 72:S209-S224. [PMID: 37888965 PMCID: PMC10669950 DOI: 10.33549/physiolres.935155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/07/2023] [Indexed: 12/01/2023] Open
Abstract
Our knowledge of tumor-infiltrating lymphocytes (TILs) is dramatically expanding. These cells have proven prognostic and therapeutic value for many cancer outcomes and potential to treat also disseminated breast, colorectal, or lung cancer. However, the therapeutical outcome of TILs is negatively affected by tumor mutational burden and neoantigens. On the other hand, it can be improved in combination with checkpoint blockade therapy. This knowledge and rapid detection techniques alongside gene editing allow us to classify and modify T cells in many ways. Hence, to tailor them precisely to the patient´s needs as to program T cell receptors to recognize specific tumor-associated neoantigens and to insert them into lymphocytes or to select tumor neoantigen-specific T cells, for the development of vaccines that recognize tumor-specific antigens in tumors or metastases. Further studies and clinical trials in the field are needed for an even better-detailed understanding of TILs interactions and aiming in the fight against multiple cancers.
Collapse
Affiliation(s)
- T Zemanek
- Lambda Life, Bratislava, Slovak Republic.
| | | | | |
Collapse
|
|
12
|
Shen MH, Liu CY, Chang KW, Lai CL, Chang SC, Huang CJ. Propolis Has an Anticancer Effect on Early Stage Colorectal Cancer by Affecting Epithelial Differentiation and Gut Immunity in the Tumor Microenvironment. Nutrients 2023; 15:4494. [PMID: 37960147 PMCID: PMC10648826 DOI: 10.3390/nu15214494] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/10/2023] [Accepted: 10/20/2023] [Indexed: 11/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and is the second leading cause of cancer-related death in the world. Due to the westernization of diets, young patients with CRC are often diagnosed at advanced stages with an associated poor prognosis. Improved lifestyle choices are one way to minimize CRC risk. Among diet choices is the inclusion of bee propolis, long recognized as a health supplement with anticancer activities. Understanding the effect of propolis on the gut environment is worth exploring, and especially its associated intratumoral immune changes and its anticancer effect on the occurrence and development of CRC. In this study, early stage CRC was induced with 1,2-dimethylhydrazine (DMH) and dextran sulfate sodium (DSS) for one month in an animal model, without and with propolis administration. The phenotypes of early stage CRC were evaluated by X-ray microcomputed tomography and histologic examination. The gut immunity of the tumor microenvironment was assessed by immunohistochemical staining for tumor-infiltrating lymphocytes (TILs) and further comparative quantification. We found that the characteristics of the CRC mice, including the body weight, tumor loading, and tumor dimensions, were significantly changed due to propolis administration. With further propolis administration, the CRC tissues of DMH/DSS-treated mice showed decreased cytokeratin 20 levels, a marker for intestinal epithelium differentiation. Additionally, the signal intensity and density of CD3+ and CD4+ TILs were significantly increased and fewer forkhead box protein P3 (FOXP3) lymphocytes were observed in the lamina propria. In conclusion, we found that propolis, a natural supplement, potentially prevented CRC progression by increasing CD3+ and CD4+ TILs and reducing FOXP3 lymphocytes in the tumor microenvironment of early stage CRC. Our study could suggest a promising role for propolis in complementary medicine as a food supplement to decrease or prevent CRC progression.
Collapse
Affiliation(s)
- Ming-Hung Shen
- Department of Surgery, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 243089, Taiwan;
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan;
| | - Chih-Yi Liu
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan;
- Department of Pathology, Sijhih Cathay General Hospital, New Taipei City 221037, Taiwan
| | - Kang-Wei Chang
- Taipei Neuroscience Institute, Taipei Medical University, Taipei City 110301, Taiwan;
- Laboratory Animal Center, Taipei Medical University, Taipei City 110301, Taiwan
| | - Ching-Long Lai
- Division of Basic Medical Sciences, Department of Nursing, Chang Gung University of Science and Technology, Taoyuan City 333324, Taiwan;
- Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan City 333324, Taiwan
| | - Shih-Chang Chang
- Division of Colorectal Surgery, Department of Surgery, Cathay General Hospital, Taipei City 106438, Taiwan;
| | - Chi-Jung Huang
- Department of Biochemistry, National Defense Medical Center, Taipei City 114201, Taiwan
- Department of Medical Research, Cathay General Hospital, Taipei City 106438, Taiwan
| |
Collapse
|
|
13
|
Stepanyan A, Fassan M, Spolverato G, Castagliuolo I, Scarpa M, Scarpa M. IMMUNOREACT 0: Biopsy-based immune biomarkers as predictors of response to neoadjuvant therapy for rectal cancer-A systematic review and meta-analysis. Cancer Med 2023; 12:17878-17890. [PMID: 37537787 PMCID: PMC10523971 DOI: 10.1002/cam4.6423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 07/03/2023] [Accepted: 07/26/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND The main therapy for rectal cancer patients is neoadjuvant therapy (NT) followed by surgery. Immune biomarkers are emerging as potential predictors of the response to NT. We performed a meta-analysis to estimate their predictive significance. METHODS A systematic literature search of PubMed, Ovid MEDLINE and EMBASE databases was performed to identify eligible studies. Studies on patients with rectal cancer undergoing NT in which the predictive significance of at least one of the immunological markers of interest was assessed by immunohistochemistry (IHC) in pretreatment biopsies were included. RESULTS Seventeen studies reporting sufficient data met the inclusion criteria for meta-analysis. High levels of total CD3+, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs), as well as stromal and intraepithelial CD8+ compartments, significantly predicted good pathological response to NT. Moreover, high levels of total (tumoral and immune cell expression) PD-L1 resulted associated to a good pathological response. On the contrary, high levels of intraepithelial CD4+ TILs were correlated with poor pathological response. FoxP3+ TILs, tumoral PD-L1 and CTLA-4 were not correlated to the treatment response. CONCLUSION This meta-analysis indicated that high-density TILs might be predictive biomarkers of pathological response in patients that underwent NT for rectal cancer.
Collapse
Affiliation(s)
- Astghik Stepanyan
- UOC Chirurgia Generale 3Azienda Ospedale‐Università PadovaPaduaItaly
| | - Matteo Fassan
- Department of Medicine DIMEDUniversity of PaduaPaduaItaly
- Veneto Institute of Oncology IOV‐IRCCSPaduaItaly
| | - Gaya Spolverato
- UOC Chirurgia Generale 3Azienda Ospedale‐Università PadovaPaduaItaly
| | | | - Melania Scarpa
- Immunology and Molecular Oncology Diagnostics UnitVeneto Institute of Oncology IOV‐IRCCSPaduaItaly
| | - Marco Scarpa
- UOC Chirurgia Generale 3Azienda Ospedale‐Università PadovaPaduaItaly
| |
Collapse
|
|
14
|
Bonilla CE, Montenegro P, O’Connor JM, Hernando-Requejo O, Aranda E, Pinto Llerena J, Llontop A, Gallardo Escobar J, Díaz Romero MDC, Bautista Hernández Y, Graña Suárez B, Batagelj EJ, Wali Mushtaq A, García-Foncillas J. Ibero-American Consensus Review and Incorporation of New Biomarkers for Clinical Practice in Colorectal Cancer. Cancers (Basel) 2023; 15:4373. [PMID: 37686649 PMCID: PMC10487247 DOI: 10.3390/cancers15174373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Advances in genomic technologies have significantly improved the management of colorectal cancer (CRC). Several biomarkers have been identified in CRC that enable personalization in the use of biologic agents that have shown to enhance the clinical outcomes of patients. However, technologies used for their determination generate massive amounts of information that can be difficult for the clinician to interpret and use adequately. Through several discussion meetings, a group of oncology experts from Spain and several Latin American countries reviewed the latest literature to provide practical recommendations on the determination of biomarkers in CRC based on their clinical experience. The article also describes the importance of looking for additional prognostic biomarkers and the use of histopathology to establish an adequate molecular classification. Present and future of immunotherapy biomarkers in CRC patients are also discussed, together with several techniques for marker determination, including liquid biopsy, next-generation sequencing (NGS), polymerase chain reaction (PCR), and fecal immunohistochemical tests. Finally, the role of Molecular Tumor Boards in the diagnosis and treatment of CRC is described. All of this information will allow us to highlight the importance of biomarker determination in CRC.
Collapse
Affiliation(s)
- Carlos Eduardo Bonilla
- Fundación CTIC—Centro de Tratamiento e Investigación sobre Cáncer, Bogotá 1681442, Colombia
| | - Paola Montenegro
- Institución AUNA OncoSalud e Instituto Nacional de Enfermedades Neoplásicas, Lima 15023, Peru
| | | | | | - Enrique Aranda
- Departamento de Oncología Médica, Hospital Reina Sofía, IMIBIC, UCO, CIBERONC, 14004 Cordoba, Spain;
| | | | - Alejandra Llontop
- Instituto de Oncología Ángel H. Roffo, Ciudad Autónoma de Buenos Aires C1437FBG, Argentina
| | | | | | | | - Begoña Graña Suárez
- Servicio de Oncología Médica, Hospital Universitario de A Coruña, Servicio Galego de Saúde (SERGAS), 15006 A Coruña, Spain;
| | | | | | - Jesús García-Foncillas
- Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
| |
Collapse
|
|
15
|
Wang YM, Cai W, Xue QM, Zhang JY, Zhou L, Xiong SY, Deng H. Prognostic role of different PD-L1 expression patterns and tumor-infiltrating lymphocytes in high-grade serous ovarian cancer: a systematic review and meta-analysis. Front Immunol 2023; 14:1234894. [PMID: 37654479 PMCID: PMC10465691 DOI: 10.3389/fimmu.2023.1234894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/31/2023] [Indexed: 09/02/2023] Open
Abstract
Background The prognostic value of programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSOC) remains a controversial topic in the research field. To comprehensively assess the importance of PD-L1 and TILs in this particular subtype of ovarian cancer, we performed a meta-analysis. Methods We conducted a comprehensive search of PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases up to December 25, 2022. The association between PD-L1, TILs, and survival outcomes was evaluated using the combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). Results This meta-analysis comprised 11 trials involving a total of 1746 cases. The results revealed no significant association between PD-L1 expression in tumor cells (TCs) and overall survival (OS, HR = 0.76, 95% CI: 0.52-1.09, p = 0.136) or progression-free survival (PFS, HR = 0.71, 95% CI: 0.4 -1.24, p = 0.230). Nevertheless, a correlation was observed between PD-L1 expression in immune cells (ICs) and OS (HR = 0.73, 95% CI: 0.55-0.97, p = 0.031). Furthermore, the presence of CD8+ and PD-1+ TILs was found to significantly enhance OS (HR = 0.70, 95% CI = 0.55-0.87, p = 0.002; HR = 0.57, 95% CI = 0.40-0.80, p = 0.001, respectively) and PFS (HR = 0.62, 95% CI = 0.41-0.92, p = 0.019; HR = 0.52, 95% CI = 0.35-0.78, p = 0.002, respectively), whereas the presence of CD3+ and CD4+ TILs was positively associated with OS (HR = 0.50, 95% CI = 0.29-0.87, p = 0.014; HR = 0.55, 95% CI = 0.34-0.91, p = 0.020, respectively). Conclusion This study indicates a positive correlation between ICs-derived PD-L1 and survival, while no significant correlation was observed between TCs-derived PD-L1 and prognosis. These results highlight the importance of studying PD-L1 expression in ICs as a prognostic predictor. In addition, the presence of TILs was found to significantly improve patient survival, suggesting that TILs may be a valuable prognostic biomarker. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022366411.
Collapse
Affiliation(s)
- Ye-Min Wang
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Cai
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qing-Ming Xue
- Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jin-Yao Zhang
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lv Zhou
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Su-Yi Xiong
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huan Deng
- Department of Pathology, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
16
|
Dickerson LK, Carter JA, Kohli K, Pillarisetty VG. Emerging interleukin targets in the tumour microenvironment: implications for the treatment of gastrointestinal tumours. Gut 2023; 72:1592-1606. [PMID: 37258094 DOI: 10.1136/gutjnl-2023-329650] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/15/2023] [Indexed: 06/02/2023]
Abstract
The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.
Collapse
Affiliation(s)
| | - Jason A Carter
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
| | - Karan Kohli
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
- Flatiron Bio, Palo Alto, California, USA
| | - Venu G Pillarisetty
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
17
|
Uhlik M, Pointing D, Iyer S, Ausec L, Štajdohar M, Cvitkovič R, Žganec M, Culm K, Santos VC, Pytowski B, Malafa M, Liu H, Krieg AM, Lee J, Rosengarten R, Benjamin L. Xerna™ TME Panel is a machine learning-based transcriptomic biomarker designed to predict therapeutic response in multiple cancers. Front Oncol 2023; 13:1158345. [PMID: 37251949 PMCID: PMC10213262 DOI: 10.3389/fonc.2023.1158345] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Most predictive biomarkers approved for clinical use measure single analytes such as genetic alteration or protein overexpression. We developed and validated a novel biomarker with the aim of achieving broad clinical utility. The Xerna™ TME Panel is a pan-tumor, RNA expression-based classifier, designed to predict response to multiple tumor microenvironment (TME)-targeted therapies, including immunotherapies and anti-angiogenic agents. Methods The Panel algorithm is an artificial neural network (ANN) trained with an input signature of 124 genes that was optimized across various solid tumors. From the 298-patient training data, the model learned to discriminate four TME subtypes: Angiogenic (A), Immune Active (IA), Immune Desert (ID), and Immune Suppressed (IS). The final classifier was evaluated in four independent clinical cohorts to test whether TME subtype could predict response to anti-angiogenic agents and immunotherapies across gastric, ovarian, and melanoma datasets. Results The TME subtypes represent stromal phenotypes defined by angiogenesis and immune biological axes. The model yields clear boundaries between biomarker-positive and -negative and showed 1.6-to-7-fold enrichment of clinical benefit for multiple therapeutic hypotheses. The Panel performed better across all criteria compared to a null model for gastric and ovarian anti-angiogenic datasets. It also outperformed PD-L1 combined positive score (>1) in accuracy, specificity, and positive predictive value (PPV), and microsatellite-instability high (MSI-H) in sensitivity and negative predictive value (NPV) for the gastric immunotherapy cohort. Discussion The TME Panel's strong performance on diverse datasets suggests it may be amenable for use as a clinical diagnostic for varied cancer types and therapeutic modalities.
Collapse
Affiliation(s)
- Mark Uhlik
- OncXerna Therapeutics, Inc., Waltham, MA, United States
| | | | - Seema Iyer
- OncXerna Therapeutics, Inc., Waltham, MA, United States
| | - Luka Ausec
- Genialis, Inc., Boston, MA, United States
| | | | | | | | - Kerry Culm
- OncXerna Therapeutics, Inc., Waltham, MA, United States
| | | | | | - Mokenge Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Hong Liu
- Checkmate Pharmaceuticals, Inc., Cambridge, MA, United States
| | - Arthur M. Krieg
- Checkmate Pharmaceuticals, Inc., Cambridge, MA, United States
| | - Jeeyun Lee
- Department of Hematology and Oncology, Samsung Medical Center, Seoul, Republic of Korea
| | | | | |
Collapse
|
|
18
|
Wurschi GW, Güllmar D, Gaßler N, Clement J, Kesselmeier M, Müller-Wurschi JJ, Settmacher U, Mothes H, Helfritzsch H, Liebe Y, Franiel T, Mäurer MA, Ernst T, Nicolay NH, Wittig A. Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO). Medicine (Baltimore) 2023; 102:e33575. [PMID: 37115093 PMCID: PMC10146036 DOI: 10.1097/md.0000000000033575] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023] Open
Abstract
INTRODUCTION Conducting neoadjuvant chemoradiotherapy (CRT) and additional preoperative consolidating chemotherapy (CTx), that is, total neoadjuvant therapy (TNT), improves local control and complete response (CR) rates in locally advanced rectal cancer (LARC), putting the focus on organ preservation concepts. Therefore, assessing response before surgery is crucial. Some LARC patients would either not benefit from intensification by TNT or may reach CR, making resection not mandatory. Treatment of LARC should therefore be based on patient individual risk and response to avoid overtreatment.The "PRIMO" pilot study aims to determine early response assessment to form a basis for development and validation of a noninvasive response prediction model by a subsequent prospective multicenter trial, which is highly needed for individual, response-driven therapy adaptions. METHODS PRIMO is a prospective observational cohort study including adult patients with LARC receiving neoadjuvant CRT. At least 4 multiparametric magnetic resonance imaging (MRI) scans (diffusion-weighted imaging [DWI] and hypoxia-sensitive sequences) as well as repeated blood samples in order to analyze circulating tumor cells (CTC) and cell-free tumor DNA (ctDNA) are scheduled. Pelvic radiotherapy (RT, 50.4 Gy) will be performed in combination with a 5-fluorouracil/oxaliplatin regimen in all patients (planned: N = 50), succeeded by consolidation CTx (FOLFOX4) if feasible. Additional (immuno)histochemical markers, such as tumor-infiltrating lymphocytes (TIL) and programmed death ligand 1 (PD-L1) status will be analyzed before and after CRT. Routine resection is scheduled subsequently, nonoperative management is offered alternatively in case of clinical CR (cCR).The primary endpoint is pathological response; secondary endpoints comprise longitudinal changes in MRI as well as in CTCs and TIL. These are evaluated for early response prediction during neoadjuvant therapy, in order to develop a noninvasive response prediction model for subsequent analyses. DISCUSSION Early response assessment is the key in differentiating "good" and "bad" responders during neoadjuvant CRT, allowing adaption of subsequent therapies (additional consolidating CTx, organ preservation). This study will contribute in this regard, by advancing MR imaging and substantiating new surrogate markers. Adaptive treatment strategies might build on these results in further studies.
Collapse
Affiliation(s)
- Georg W. Wurschi
- Department of Radiotherapy and Radiation Oncology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany
- Clinician Scientist Program, Interdisciplinary Center for Clinical Research (IZKF), Jena University Hospital, Jena, Germany
| | - Daniel Güllmar
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology (IDIR), Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
| | - Nikolaus Gaßler
- Section of Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena, Germany
| | - Joachim Clement
- Department of Hematology and Medical Oncology, Jena University Hospital, Jena, Germany
| | - Miriam Kesselmeier
- Institute of Medical Statistics, Computer and Data Sciences (IMSID), Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany
| | | | - Utz Settmacher
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | - Henning Mothes
- Department of General, Visceral and Vascular Surgery, Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany
| | - Herry Helfritzsch
- Department of General, Visceral and Thoracic Surgery, Thuringia-Clinic Saalfeld Georgius Agricola, Saalfeld, Germany
| | - Yves Liebe
- Department of General and Visceral Surgery, SRH Klinikum Burgenlandkreis Naumburg, Naumburg, Germany
| | - Tobias Franiel
- Institute of Diagnostic and Interventional Radiology (IDIR), Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany
| | - Matthias A. Mäurer
- Department of Radiotherapy and Radiation Oncology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany
- Clinician Scientist Program, Interdisciplinary Center for Clinical Research (IZKF), Jena University Hospital, Jena, Germany
| | - Thomas Ernst
- University Tumor Center (UTC), Jena University Hospital, Jena, Germany
| | - Nils H. Nicolay
- Department of Radiation Oncology, University of Leipzig Medical Center, Leipzig, Germany
| | - Andrea Wittig
- Department of Radiotherapy and Radiation Oncology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany
| |
Collapse
|
|
19
|
Han Y, Cheng L, Huang G, Zhong G, Li J, Yuan X, Liu H, Li J, Zhou J, Cai M. Weakly supervised semantic segmentation of histological tissue via attention accumulation and pixel-level contrast learning. Phys Med Biol 2023; 68. [PMID: 36577142 DOI: 10.1088/1361-6560/acaeee] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/28/2022] [Indexed: 12/29/2022]
Abstract
Objective. Histopathology image segmentation can assist medical professionals in identifying and diagnosing diseased tissue more efficiently. Although fully supervised segmentation models have excellent performance, the annotation cost is extremely expensive. Weakly supervised models are widely used in medical image segmentation due to their low annotation cost. Nevertheless, these weakly supervised models have difficulty in accurately locating the boundaries between different classes of regions in pathological images, resulting in a high rate of false alarms Our objective is to design a weakly supervised segmentation model to resolve the above problems.Approach. The segmentation model is divided into two main stages, the generation of pseudo labels based on class residual attention accumulation network (CRAANet) and the semantic segmentation based on pixel feature space construction network (PFSCNet). CRAANet provides attention scores for each class through the class residual attention module, while the Attention Accumulation (AA) module overlays the attention feature maps generated in each training epoch. PFSCNet employs a network model containing an inflated convolutional residual neural network and a multi-scale feature-aware module as the segmentation backbone, and proposes dense energy loss and pixel clustering modules are based on contrast learning to solve the pseudo-labeling-inaccuracy problem.Main results. We validate our method using the lung adenocarcinoma (LUAD-HistoSeg) dataset and the breast cancer (BCSS) dataset. The results of the experiments show that our proposed method outperforms other state-of-the-art methods on both datasets in several metrics. This suggests that it is capable of performing well in a wide variety of histopathological image segmentation tasks.Significance. We propose a weakly supervised semantic segmentation network that achieves approximate fully supervised segmentation performance even in the case of incomplete labels. The proposed AA and pixel-level contrast learning also make the edges more accurate and can well assist pathologists in their research.
Collapse
Affiliation(s)
- Yongqi Han
- School of Computer Science and Technology, Guangdong University of Technology, Guangzhou 510006, People's Republic of China
| | - Lianglun Cheng
- School of Computer Science and Technology, Guangdong University of Technology, Guangzhou 510006, People's Republic of China
| | - Guoheng Huang
- School of Computer Science and Technology, Guangdong University of Technology, Guangzhou 510006, People's Republic of China
| | - Guo Zhong
- School of Information Science and Technology, Guangdong University of Foreign Studies, Guangzhou 510420, People's Republic of China
| | - Jiahua Li
- School of Computer Science and Technology, Guangdong University of Technology, Guangzhou 510006, People's Republic of China
| | - Xiaochen Yuan
- Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, People's Republic of China
| | - Hongrui Liu
- Department of Industrial and Systems Engineering, San Jose State University, CA 95192, United States of America
| | - Jiao Li
- Department of Radiology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People's Republic of China
| | - Jian Zhou
- Department of Medical Imaging, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People's Republic of China
| | - Muyan Cai
- Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People's Republic of China
| |
Collapse
|
|
20
|
Immunological and Clinico-Molecular Features of Tumor Border Configuration in Colorectal Cancer. J Am Coll Surg 2023; 236:126-134. [PMID: 36519916 DOI: 10.1097/xcs.0000000000000440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Infiltrating tumor border configuration (ITBC) portends a poor prognosis compared with pushing tumor border configuration (PTBC) in colorectal cancer. The tumor and its surrounding immune microenvironment of tumor border configuration is not well-characterized. We aim to elucidate the differences in expression of molecular markers between the 2 groups using tissue microarray (TMA). STUDY DESIGN Immunohistochemistry was performed on TMAs of surgical pathology specimens obtained from colorectal cancer patients consecutively operated at our institution from 2004 to 2015. TMAs were stained for immune cells (CD8, FOXP3, LAG3, PU1, CD163, and PDL1); HLA II, beta 2 microglobulin, and HC10 on tumor cells; BRAFV600E mutation; and DNA mismatch repair proteins (MMR) status. Patients who received neoadjuvant therapy were excluded. RESULTS There were 646 tumors with ITBC and 310 tumors with PTBC. There was a significantly lower expression (p < 0.05) of immune components, namely CD8, FOXP3, LAG3, PU1, PDL1 immune cells, and Beta-2 Microglobulin on tumor cells in the tumors with ITBC compared with PTBC, except CD163 immune cells, and HC10 and HLAII on tumor cells. Tumors with ITBC were less likely to be associated with BRAFV600E mutations and deficient MMR proteins (p < 0.001). On analyzing MMR-proficient tumors separately, we could not find any difference in the expression of any molecular marker (including BRAF), except a lower expression of PDL1 immune cells in tumors with ITBC (p < 0.001). CONCLUSIONS Colorectal tumors with ITBC are associated with a generalized low immune microenvironment and low rates of BRAFV600E mutation compared with tumors with PTBC. However, the molecular expression of tumor border configuration seems confounded by the MMR molecular signature. MMR-proficient colorectal tumors with ITBC are associated with a lower expression of only PDL1 immune cells among all immune markers examined.
Collapse
|
|
21
|
Lisanti C, Basile D, Garattini SK, Parnofiello A, Corvaja C, Cortiula F, Bertoli E, Ongaro E, Foltran L, Casagrande M, Di Nardo P, Cardellino GG, Fasola G, Buonadonna A, Pella N, Aprile G, Puglisi F. The SAFFO Study: Sex-Related Prognostic Role and Cut-Off Definition of Monocyte-to-Lymphocyte Ratio (MLR) in Metastatic Colorectal Cancer. Cancers (Basel) 2022; 15:cancers15010175. [PMID: 36612170 PMCID: PMC9818397 DOI: 10.3390/cancers15010175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/12/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Background: Emerging data suggest that gender-related immune system composition affects both immune response and efficacy of immunotherapy in cancer patients (pts). This study aimed to investigate the sex-related prognostic role of MLR in metastatic colorectal cancer (mCRC) pts. Methods: We analyzed a retrospective consecutive cohort of 490 mCRC patients treated from 2009 to 2018 at the Oncology Departments of Aviano and Pordenone (training set) and Udine (validation set), Italy. The prognostic impact of MLR on overall survival (OS) was evaluated with uni- and multivariable Cox regression models. The best cut-off value to predict survival was defined through ROC analyses. Results: Overall, we identified 288 males (59%) and 202 females (41%); 161 patients (33%) had a right-sided, 202 (42%) a left-sided primary, and 122 (25%) a rectal tumor. Interestingly, gender was associated with MLR (p = 0.004) and sidedness (p = 0.006). The obtained cut-off value for MLR in females and males was 0.27 and 0.49, respectively. According to univariate analysis of the training set, MLR (HR 9.07, p ≤ 0.001), MLR > 0.27 in females (HR 1.95, p = 0.003), and MLR > 0.49 in males (HR 2.65, p = 0.010) were associated with poorer OS, which was also confirmed in the validation set. In multivariate analysis, MLR > 0.27 in females (HR 2.77, p = 0.002), MLR > 0.49 in males (HR 5.39, p ≤ 0.001), BRAF mutation (HR 3.38, p ≤ 0.001), and peritoneal metastases (HR 2.50, p = 0.003) were still independently associated with worse OS. Conclusions: Males and females have a different immune response. Our study showed that high MLR, both in males and females, is an unfavorable Independent prognostic factor. Further prospective studies are needed to confirm these data.
Collapse
Affiliation(s)
- Camilla Lisanti
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
- Correspondence: ; Tel.: +39-0434-659136
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, 88900 Crotone, Italy
| | | | - Annamaria Parnofiello
- Sandro Pitigliani Medical Oncology Department, Hospital of Prato, 59100 Prato, Italy
| | - Carla Corvaja
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | | | - Elisa Bertoli
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | - Elena Ongaro
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | | | - Paola Di Nardo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | | | - Gianpiero Fasola
- Department of Oncology, ASUFC University Hospital, 33100 Udine, Italy
| | - Angela Buonadonna
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Nicoletta Pella
- Department of Oncology, ASUFC University Hospital, 33100 Udine, Italy
| | - Giuseppe Aprile
- Department of Medical Oncology, San Bortolo Hospital, Azienda ULSS8 Berica, 36100 Vicenza, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| |
Collapse
|
|
22
|
Zhang W, Shi Y, Niu S, Li L, Lin L, Gao X, Cai W, Chen Y, Zhong Y, Tang D, Tang M, Dai Y. Integrated computer analysis and a self-built Chinese cohort study identified GSTM2 as one survival-relevant gene in human colon cancer potentially regulating immune microenvironment. Front Oncol 2022; 12:881906. [PMID: 36263204 PMCID: PMC9574330 DOI: 10.3389/fonc.2022.881906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
According to a recent report by GLOBOCAN, colorectal cancer is the third most common and second most deadly cancer in 2020. In our previous proteomic study, we found that the expression of GSTM2 in colon tissues was significantly lower than that in para-cancer tissues, and its lower expression was associated with reduced overall survival rate of patients, suggesting that this gene might play a role in the occurrence of colon cancer. As a member of the detoxifying enzyme family, GSTM2 is likely to play an important role in the initiation of tumors. Whereas, the functions of GSTM2 in colon cancer are barely known. In this study, using the RNA-Seq datasets of colon cancer patients from public database (ntumor = 457, nnormal = 41), we confirmed the reduced expression of GSTM2 and its prognostic value in colon cancer. Furthermore, we used our own Chinese cohort (ntumor = 100, nnormal = 72) verified the lower GSTM2 expression in colon cancer, and also its effects on patient prognosis. Subsequently, we uncovered two potential reasons for the lower expression of GSTM2 in colon cancer tissues, including the deep deletion of GSTM2 on genome, and the up-regulation of RAD21 or SP1. Moreover, we disclosed that GSTM2 might be involved in several immune-related pathways in colon cancer, such as chemokine signaling and leukocyte transendothelial migration. Finally, we revealed that the GSTM2 expression was closely related to the immune-related scores of colon cancer and the infiltration ratios of various immune cells, suggesting that GSTM2 might regulate the development of colon cancer by modulating immune microenvironment. In conclusion, we uncovered the prognostic value of GSTM2 based on the public data and our own data, revealed its potential regulatory role in tumor immune microenvironment, and disclosed the probable reasons for its lower expression in colon cancer. The findings of our study provide a potential prognostic biomarker and drug target for clinical diagnosis and treatment of colon cancer.
Collapse
Affiliation(s)
- Wei Zhang
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
- South China Hospital, Health Science Center, Shenzhen University, Shenzhen, China
- Medical School, Nanchang Institute of Technology, Nanchang, China
| | - Yutong Shi
- Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Shumeng Niu
- Laboratory Department, Shanghai Hongkou Jiangwan Hospital, Shanghai, China
| | - Lintai Li
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Liewen Lin
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Xucan Gao
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Wanxia Cai
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Yumei Chen
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Yafang Zhong
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
| | - Donge Tang
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
- *Correspondence: Yong Dai, ; ; Donge Tang, ; Min Tang,
| | - Min Tang
- Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
- *Correspondence: Yong Dai, ; ; Donge Tang, ; Min Tang,
| | - Yong Dai
- Clinical Medical Research Center, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China
- *Correspondence: Yong Dai, ; ; Donge Tang, ; Min Tang,
| |
Collapse
|
|
23
|
High DHCR7 Expression Predicts Poor Prognosis for Cervical Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8383885. [PMID: 36164611 PMCID: PMC9508458 DOI: 10.1155/2022/8383885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 07/19/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022]
Abstract
DHCR7 is a rate-limiting enzyme in cholesterol synthesis. The expression pattern and prognostic value of DHCR7 in cervical cancer are unknown. We investigated the relationship between DHCR7 expression and clinicopathological features of cervical cancer patients. The dataset was acquired from TCGA database. The Wilcoxon rank sum test was used to explore DHCR7 expression level in cervical cancer. The Kruskal-Wallis test and the logistic regression were performed to estimate the association between the DHCR7 and clinical features. The Kaplan-Meier and Cox regression analyses were used to evaluate factors that affect cervical cancer prognosis. GSEA was used to screen the DHCR7-related pathways. We found that DHCR7 was increased in cervical cancer samples and increased DHCR7 was correlated with advanced T stage, lymph node invasion, and clinical stage (P < 0.05). Patients with elevated DHCR7 levels had poorer overall survival (P = 0.021), progression-free interval (P = 0.002), and disease-specific survival (P = 0.005). Cox analysis revealed that DHCR7 was an independent prognostic factor in cervical cancer (P = 0.005). WNT activated receptor activity, G2/M checkpoint, mTORC1 signaling, KRAS signaling, regulation of cholesterol biosynthetic, FGF signaling, T-cell receptor signaling, JAK/STAT signaling cascade T cell activation, and macrophage migration were enriched in high DHCR7 phenotype. Our data also showed that DHCR7 moderately correlates with T-cell infiltration, including CD8+ T-cells. Conclusion. Increased DHCR7 expression is associated with poor survival in cervical cancer.
Collapse
|
|
24
|
Bell PD, Pai RK. Immune Response in Colorectal Carcinoma: A Review of Its Significance as a Predictive and Prognostic Biomarker. Histopathology 2022; 81:696-714. [PMID: 35758208 DOI: 10.1111/his.14713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/02/2022] [Accepted: 06/06/2022] [Indexed: 11/30/2022]
Abstract
Colorectal carcinoma is a leading cause of cancer-related death worldwide. There is significant prognostic heterogeneity in stage II and III tumours, necessitating the development of new biomarkers to better identify patients at risk of disease progression. Recently, the tumour immune environment, particularly the type and quantity of T lymphocytes, has been shown to be a useful biomarker in predicting prognosis for patients with colorectal carcinoma. In this review, the significance of the immune response in colorectal carcinoma, including its influence on prognosis and response to therapy, will be detailed.
Collapse
Affiliation(s)
- Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Centre, Pittsburgh, PA, 15213, USA
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Centre, Pittsburgh, PA, 15213, USA
| |
Collapse
|
|
25
|
Qin M, Chen G, Hou J, Wang L, Wang Q, Wang L, Jiang D, Hu Y, Xie B, Chen J, Wei H, Xu G. Tumor-infiltrating lymphocyte: features and prognosis of lymphocytes infiltration on colorectal cancer. Bioengineered 2022; 13:14872-14888. [PMID: 36633318 PMCID: PMC9995135 DOI: 10.1080/21655979.2022.2162660] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) are vital elements of the tumor microenvironment (TME), and the anti-tumor activity of TILs on colorectal cancer (CRC) has been a topic of concern. However, the characteristics and prognosis of the various types of lymphocyte infiltration in CRC have not been fully explained. Our study aimed to identify distinct features and prognosis of TILs. We integrated multiple-cohort databases to illustrate the features, proportions, and prognosis of TILs on CRC. We found that macrophages were significantly enriched in CRC. When we used the scRNA-seq database to further evaluate the proportion of TILs, we noticed markedly higher numbers of CD4 + T cell, B cell, and CD8 + T cell in four Gene Expression Omnibus Series (GSE) CRC cohorts. Interestingly, we found that the infiltrating level of TIL subgroups from highest to lowest is always dendritic cells, CD8 + T cells, CD4 + T cells, neutrophils, B cells, and macrophages; the proportion of infiltration is largely constant regardless of mutations in specific genes or somatic copy number variation (sCNV). In addition, the data corroborated that CD4+ TILs and CD8+ TILs have certain application values in the prognosis of CRCs, and age negatively related to CD8+ TILs and B plasma infiltration. Finally, patients with CRC who are older than 70 years have a better response to immune-checkpoint blockade.
Collapse
Affiliation(s)
- Miao Qin
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Gang Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jinxia Hou
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Li Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qunfeng Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Lina Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Dan Jiang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Institute of Clinical Laboratory, Guangdong Medical University, Dongguan, China
| | - Ye Hu
- Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bei Xie
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jing Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Hulai Wei
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Guangxian Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Institute of Clinical Laboratory, Guangdong Medical University, Dongguan, China
| |
Collapse
|
|
26
|
Multi-layer pseudo-supervision for histopathology tissue semantic segmentation using patch-level classification labels. Med Image Anal 2022; 80:102487. [PMID: 35671591 DOI: 10.1016/j.media.2022.102487] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 05/07/2022] [Accepted: 05/20/2022] [Indexed: 01/15/2023]
Abstract
Tissue-level semantic segmentation is a vital step in computational pathology. Fully-supervised models have already achieved outstanding performance with dense pixel-level annotations. However, drawing such labels on the giga-pixel whole slide images is extremely expensive and time-consuming. In this paper, we use only patch-level classification labels to achieve tissue semantic segmentation on histopathology images, finally reducing the annotation efforts. We propose a two-step model including a classification and a segmentation phases. In the classification phase, we propose a CAM-based model to generate pseudo masks by patch-level labels. In the segmentation phase, we achieve tissue semantic segmentation by our propose Multi-Layer Pseudo-Supervision. Several technical novelties have been proposed to reduce the information gap between pixel-level and patch-level annotations. As a part of this paper, we introduce a new weakly-supervised semantic segmentation (WSSS) dataset for lung adenocarcinoma (LUAD-HistoSeg). We conduct several experiments to evaluate our proposed model on two datasets. Our proposed model outperforms five state-of-the-art WSSS approaches. Note that we can achieve comparable quantitative and qualitative results with the fully-supervised model, with only around a 2% gap for MIoU and FwIoU. By comparing with manual labeling on a randomly sampled 100 patches dataset, patch-level labeling can greatly reduce the annotation time from hours to minutes. The source code and the released datasets are available at: https://github.com/ChuHan89/WSSS-Tissue.
Collapse
|
|
27
|
Deng T, Liu Y, Zhuang J, Tang Y, Huo Q. ASPM Is a Prognostic Biomarker and Correlates With Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma. Front Oncol 2022; 12:632042. [PMID: 35515103 PMCID: PMC9065448 DOI: 10.3389/fonc.2022.632042] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Background Abnormal spindle microtubule assembly (ASPM) is a centrosomal protein and that is related to a poor clinical prognosis and recurrence. However, the relationship between ASPM expression, tumor immunity, and the prognosis of different cancers remains unclear. Methods ASPM expression and its influence on tumor prognosis were analyzed using the Tumor Immune Estimation Resource (TIMER), UALCAN, OncoLnc, and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The relationship between ASPM expression and tumor immunity was analyzed using the TIMER and GEPIA databases, and the results were further verified using qPCR, western blot, and multiplex quantitative immuno fluorescence. Results The results showed that ASPM expression was significantly higher in most cancer tissues than in corresponding normal tissues, including kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and breast invasive carcinoma (BRCA). ASPM expression was significantly higher in late-stage cancers than in early-stages cancers (e.g., KIRC, KIRP, LIHC, LUAD, and BRCA; p < 0.05), demonstrating a possible role of ASPM in cancer progression and invasion. Moreover, our data showed that high ASPM expression was associated with poor overall survival, and disease-specific survival in KIRC and LIHC (p < 0.05). Besides, Cox hazard regression analysis results showed that ASPM may be an independent prognostic factor for KIRC and LIHC. ASPM expression showed a strong correlation with tumor-infiltrating B cells, CD8+ T cells, and M2 macrophages in KIRC and LIHC. Conclusions These findings demonstrate that the high expression of ASPM indicates poor prognosis as well as increased levels of immune cell infiltration in KIRC and LIHC. ASPM expression may serve as a novel prognostic biomarker for both the clinical outcome and immune cell infiltration in KIRC and LIHC.
Collapse
Affiliation(s)
- Tingting Deng
- Department of Otolaryngology and Geriatric Medicine, Biobank, Shenzhen Institute of Translational Medicine, Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yang Liu
- Department of Otolaryngology and Geriatric Medicine, Biobank, Shenzhen Institute of Translational Medicine, Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jialang Zhuang
- Department of Otolaryngology and Geriatric Medicine, Biobank, Shenzhen Institute of Translational Medicine, Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yizhe Tang
- Department of Otolaryngology and Geriatric Medicine, Biobank, Shenzhen Institute of Translational Medicine, Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China
| | - Qin Huo
- Department of Otolaryngology and Geriatric Medicine, Biobank, Shenzhen Institute of Translational Medicine, Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China
| |
Collapse
|
|
28
|
Pan J, Weng Z, Xue C, Lin B, Lin M. The Bioinformatics-Based Analysis Identifies 7 Immune-Related Genes as Prognostic Biomarkers for Colon Cancer. Front Oncol 2021; 11:726701. [PMID: 34900677 PMCID: PMC8663025 DOI: 10.3389/fonc.2021.726701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Colon cancer poses a great threat to human health. Currently, there is no effective treatment for colon cancer due to its complex causative factors. Immunotherapy has now become a new method for tumor treatment. In this study, 487 DEGs were screened from The Cancer Genome Atlas (TCGA) database and ImmPort database, and GeneOntology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed. Hierarchical clustering of all samples revealed a significant correlation between colon cancer and immunity. The weighted gene co-expression network analysis (WGCNA) algorithm was used to identify key gene modules associated with immunity in colon cancer, here, module grey60 showed the highest correlation. A protein-protein interaction (PPI) network was constructed using the STRING database to screen hub genes, and subsequently, 7 immune-related genes the most closely associated with colon cancer were identified by differential expression in cancer and paracancer. Finally, a risk prediction model was developed using least absolute shrinkage and selection operator (LASSO) COX analysis, and the accuracy of the model was validated by GSE14333. This study determined that IRF4 and TNFRSF17 were immune-related genes in colon cancer, providing immune-related prognostic biomarkers for colon cancer.
Collapse
Affiliation(s)
- Jie Pan
- Department of Emergency Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zongqi Weng
- Department of Emergency Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Chaorong Xue
- Department of Emergency Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Bingqiang Lin
- Department of Emergency Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Mengxin Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, China
| |
Collapse
|
|
29
|
Möller K, Fraune C, Blessin NC, Lennartz M, Kluth M, Hube-Magg C, Lindhorst L, Dahlem R, Fisch M, Eichenauer T, Riechardt S, Simon R, Sauter G, Büscheck F, Höppner W, Matthies C, Doh O, Krech T, Marx AH, Zecha H, Rink M, Steurer S, Clauditz TS. Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer. Int Urol Nephrol 2021; 53:2493-2503. [PMID: 33797012 PMCID: PMC8599390 DOI: 10.1007/s11255-021-02841-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/17/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome. METHODS We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8+ cytotoxic cells. RESULT At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8+ lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8+ cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280). CONCLUSIONS These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.
Collapse
Affiliation(s)
- Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Linnea Lindhorst
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Roland Dahlem
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Eichenauer
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Silke Riechardt
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | | | - Cord Matthies
- Department of Urology, Bundeswehr Hospital Hamburg, Hamburg, Germany
| | - Ousman Doh
- Department of Urology, Regio Medical Center Elmshorn, Elmshorn, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrück, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Henrik Zecha
- Department of Urology, Albertinen Clinic, Hamburg, Germany
| | - Michael Rink
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| |
Collapse
|
|
30
|
High Expression Levels of SLC38A1 Are Correlated with Poor Prognosis and Defective Immune Infiltration in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2021; 2021:5680968. [PMID: 34697542 PMCID: PMC8541878 DOI: 10.1155/2021/5680968] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/17/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022]
Abstract
Solute Carrier Family 38 Member 1 (SLC38A1) is a principal transporter of glutamine and plays a crucial role in the transformation of neoplastic cells. However, the correlation between SLC38A1 expression, prognosis, and immune infiltration in hepatocellular carcinoma (HCC) has yet to be elucidated. We used two independent patient cohorts, namely, a Cancer Genome Atlas (TCGA) cohort and a Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort, to analyze the role of SLC38A1 in HCC at the mRNA and protein levels, respectively. In these two cohorts, SLC38A1 mRNA and protein expression levels were higher in HCC tissues than in adjacent nontumor tissues. Both SLC38A1 mRNA and protein expression were positively associated with clinicopathological characteristics (clinical stage, T stage, pathological grade, tumor size, and tumor thrombus), were negatively associated with survival, and were independent prognostic factors in HCC patients. Functional enrichment analyses further indicated that SLC38A1 was involved in multiple pathways related to amino acid metabolism, tumors, and immunity. High expression levels of SLC38A1 were inversely proportional to CD8+ T cells and directly proportional to macrophages M0, neutrophils, programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Moreover, we used immunohistochemical analysis of tissue samples and other online databases to further validate the expression levels and prognostic significance of SLC38A1 in HCC. Collectively, our study demonstrated that the upregulated expression of SLC38A1 was related to an unfavorable prognosis and defective immune infiltration in HCC.
Collapse
|
|
31
|
Li Y, Ma Y, Wu Z, Zeng F, Song B, Zhang Y, Li J, Lui S, Wu M. Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis. Front Immunol 2021; 12:751407. [PMID: 34659255 PMCID: PMC8511407 DOI: 10.3389/fimmu.2021.751407] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/10/2021] [Indexed: 02/05/2023] Open
Abstract
Objectives For colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint inhibitors (ICIs). Recent years, researchers considered tumor mutation burden (TMB) as another predictive biomarker which means the number of nonsynonymous mutations in cancer cells. Several studies have proven that TMB can evaluate the efficacy of ICI therapy in diverse types of cancer, especially in non-small cell lung cancer and melanoma. However, studies on the association between TMB and the response to ICI therapy in colorectal cancer alone are still lacking. In this study, we aim to verify the effect of TMB as a biomarker in predicting the efficacy of ICIs in colorectal cancer. Methods We searched the PubMed and Ovid MEDLINE databases up to May 1, 2021 and screened studies for eligibility. Thirteen studies published from 2015 to 2021 with 5062 patients were included finally. We extracted and calculated hazard ratios (HRs) and odds ratios (ORs) of overall survival (OS) and objective response rates (ORRs) and their 95% confidence intervals (95% CIs). Pooled HR and OR were evaluated to compare OS and ORR between TMB-high and TMB-low groups in colorectal cancer patients. Meanwhile, we assessed heterogeneity with the I2 statistic and p-values and performed publication bias assessments, sensitivity analyses, and subgroup analyses to search the cause of heterogeneity. Results The TMB-high patient group had a longer OS than the TMB-low patient group (HR = 0.68, 95% CI: 0.51, 0.92, p = 0.013) among colorectal cancer patients receiving ICIs. In addition, the TMB-high patient group was superior in terms of ORR (OR = 19.25, 95% CI: 10.06, 36.82, p < 0.001) compared to the TMB-low patient group. Conclusions In conclusion, this meta-analysis revealed that TMB can be used as a potential predictive biomarker of colorectal cancer patients receiving ICI therapy. Nevertheless, this finding is not stable enough. Therefore, many more randomized controlled trials are needed to prove that TMB is reliable enough to be used clinically to predict the efficacy of immunotherapy in colorectal cancer. And the most relevant biomarker remains to be determined when TMB high overlaps with other biomarkers like MSI and TILs.
Collapse
Affiliation(s)
- Yan Li
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Yiqi Ma
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Zijun Wu
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Fanxin Zeng
- Department of Clinic Medical Center, Dazhou Central Hospital, Dazhou, China.,Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Bin Song
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Yanrong Zhang
- Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Jinxing Li
- Department of Biomedical Engineering, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, United States
| | - Su Lui
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Min Wu
- Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
32
|
Zou Q, Wang X, Ren D, Hu B, Tang G, Zhang Y, Huang M, Pai RK, Buchanan DD, Win AK, Newcomb PA, Grady WM, Yu H, Luo Y. DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer. J Immunother Cancer 2021; 9:jitc-2021-002671. [PMID: 34548385 PMCID: PMC8458312 DOI: 10.1136/jitc-2021-002671] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2021] [Indexed: 01/12/2023] Open
Abstract
Background Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). Methods A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Results Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. Conclusions This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.
Collapse
Affiliation(s)
- Qi Zou
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaolin Wang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Donglin Ren
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bang Hu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guannan Tang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Zhang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meijin Huang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rish K Pai
- Department of laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.,University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.,Genomic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Polly A Newcomb
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.,Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Huichuan Yu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanxin Luo
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China .,Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
33
|
Ida S, Takahashi H, Kawabata-Iwakawa R, Mito I, Tada H, Chikamatsu K. Tissue-resident memory T cells correlate with the inflammatory tumor microenvironment and improved prognosis in head and neck squamous cell carcinoma. Oral Oncol 2021; 122:105508. [PMID: 34507204 DOI: 10.1016/j.oraloncology.2021.105508] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/29/2021] [Accepted: 08/19/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Tumor-infiltrating T cell (TIL) is a major cell type involved in tumor eradication in the tumor microenvironment (TME). Among TILs, tissue-resident memory T cells (TRMs) have been recognized as a subset capable of continuous immunosurveillance to afford long-term immunity. In the present study, we comprehensively profiled TRM in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS We analyzed RNA-sequencing (RNA-seq) data obtained from The Cancer Genome Atlas (TCGA) database. Based on the gene expression of CD69 and CD4/CD8A, we identified TRM-enriched patients and evaluated their clinical and biological significance. In addition, we analyzed peripheral blood mononuclear cells (PBMCs) obtained from 60 patients with HNSCC to evaluate the presence of TRM-like cells in the peripheral circulation. RESULTS TCGA analysis revealed that TRM-enriched tumors correlated with early T factor, human papillomavirus-positive status, the proportion of oropharynx lesion, upregulated inflammatory pathways, upregulation of immunostimulatory and immune checkpoint molecule genes, and favorable overall survival. Moreover, we clarified the presence of CD69 + TRM-like cells that highly express PD-1 and TIM-3 in the peripheral circulation of patients with HNSCC. CONCLUSION We highlighted the clinical and transcriptomic significance of TRM in patients with HNSCC. Further characterization of TRM could lead to the development of novel biomarkers, especially for immune checkpoint therapies.
Collapse
Affiliation(s)
- Shota Ida
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Hideyuki Takahashi
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Ikko Mito
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Hiroe Tada
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Kazuaki Chikamatsu
- Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| |
Collapse
|
|
34
|
Mo S, Pei Z, Dai L. Construction of a Signature Composed of 14 Immune Genes to Judge the Prognosis and Immune Infiltration of Colon Cancer. Genet Test Mol Biomarkers 2021; 25:163-178. [PMID: 33734891 DOI: 10.1089/gtmb.2020.0141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: Colon cancer (CC) is an immunogenic tumor and immune-targeting disease. In this study, we analyzed differentially expressed genes (DEGs) from the expression profile data in CC of The Cancer Genome Atlas. Methods and Results: Using univariate and multivariate Cox regression analysis, an immune gene-risk model containing 14 immune genes was established. Four hundred seventeen CC samples were divided into high-risk and low-risk groups, and Kaplan-Meier analysis revealed that high-risk score predicted poor survival. Meanwhile, we found the model was an independent prognostic factor for CC. Weighted gene coexpression network analysis was used to identify key gene modules between high- and low-risk groups. The methods of CIBERSORT and single-sample Gene Set Enrichment Analysis were used to evaluate the correlation between immune cells and our model. Conclusion: Taken together, our study suggested that the immune gene-related risk model may be developed as a potential tool in the prognostic assessment of CC.
Collapse
Affiliation(s)
- Shaocong Mo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, PR China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China
| | - Zhenle Pei
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China
| | - Leijie Dai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China
| |
Collapse
|
|
35
|
Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma. Sci Rep 2021; 11:16134. [PMID: 34373557 PMCID: PMC8352955 DOI: 10.1038/s41598-021-95718-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/28/2021] [Indexed: 01/10/2023] Open
Abstract
Head and neck squamous carcinoma (HNSCC) is highly infiltrated by immune cells, including tumor-infiltrating lymphocytes and myeloid lineage cells. In the tumor microenvironment, tumor cells orchestrate a highly immunosuppressive microenvironment by secreting immunosuppressive mediators, expressing immune checkpoint ligands, and downregulating human leukocyte antigen expression.
In the present study, we aimed to comprehensively profile the immune microenvironment of HNSCC using gene expression data obtained from public database. We calculated enrichment scores of 33 immune cell types based on gene expression data of HNSCC tissues and adjacent non-cancer tissues. Based on these scores, we performed non-supervised clustering and identified three immune signatures—cold, lymphocyte, and myeloid/dendritic cell (DC)—based on the clustering results. We then compared the clinical and biological features of the three signatures. Among HNSCC and non-cancer tissues, human papillomavirus (HPV)-positive HNSCCs exhibited the highest scores in various immune cell types, including CD4+ T cells, CD8+ T cells, B cells, plasma cells, basophils, and their subpopulations. Among the three immune signatures, the proportions of HPV-positive tumors, oropharyngeal cancers, early T tumors, and N factor positive cases were significantly higher in the lymphocyte signature than in other signatures. Among the three signatures, the lymphocyte signature showed the longest overall survival (OS), especially in HPV-positive patients, whereas the myeloid/DC signature demonstrated the shortest OS in these patients. Gene set enrichment analysis revealed the upregulation of several pathways related to inflammatory and proinflammatory responses in the lymphocyte signature. The expression of PRF1, IFNG, GZMB, CXCL9, CXCL10, PDCD1, LAG3, CTLA4, HAVCR2, and TIGIT was the highest in the lymphocyte signature. Meanwhile, the expression of PD-1 ligand genes CD274 and PDCD1LG2 was highest in the myeloid/DC signature. Herein, our findings revealed the transcriptomic landscape of the immune microenvironment that closely reflects the clinical and biological significance of HNSCC, indicating that molecular profiling of the immune microenvironment can be employed to develop novel biomarkers and precision immunotherapies for HNSCC.
Collapse
|
|
36
|
Berele BA, Cai Y, Yang G. Prognostic Value of Tumor Infiltrating Lymphocytes in Nasopharyngeal Carcinoma Patients: Meta-Analysis. Technol Cancer Res Treat 2021; 20:15330338211034265. [PMID: 34323154 PMCID: PMC8330464 DOI: 10.1177/15330338211034265] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objective: To evaluate the prognostic value of tumor infiltrating lymphocytes (TILs) in nasopharyngeal carcinoma (NPC) patients. Method: Meta-analysis was performed on eligible studies that was identified by systematic searching of Google scholar, MEDLINE, CNKI, Scopus, PubMed, PMC, Embase and Web of Science databases. The study protocol was registered in International Platform of Registered Systematic Review and Meta-Analysis Protocols-INPLASY (registration number: INPLASY202160014). Databases were searched from inception to January 20, 2020 to identify eligible studies. Those studies that evaluated survival in the form of hazard ratio (HR) in TILs of NPC patients was analyzed. All statistical analysis was performed by using STATA version 16.0 software. Result: Fourteen studies with a total of 3025 patients was analyzed. The pooled result showed that high TILs was significantly associated with favorable overall survival (OS) (HR = 0.55; 95%CI = 0.39-0.77; P = 0.001) and disease free survival (DFS) (HR = 0.60; 95%CI = 0.44-0.81; P = 0.04). Interestingly, high intratumoral TILs had relatively better OS (HR = 0.45; 95%CI = 0.35-0.58; P = 0.006) than stromal TILs (HR = 0.59; 95%CI = 0.36-0.97; P = 0.03). Moreover, an increased level of CD4+ cells infiltration was correlated with favorable OS (HR = 0.4; 95%CI = 0.18-0.85; P = 0.01). CD3+, CD8+ and FoxP3+ lymphocyte’s better prognosis was not statistically significant for OS (P = 0.09; P = 0.07; P = 0.52) and for DFS (P = 0.13; P = 0.29) respectively. However, subgroup analysis of intratumoral CD3+ (HR = 0.48; 95%CI = 0.33-0.70; P = 0.05) and intratumoral CD8+ (HR = 0.32; 95%CI = 0.16-0.62; P = 0.001) was significantly associated with improved OS, but not significant in stromal CD3+ (HR = 0.66; 95%CI = 0.20-2.20; P = 0.62). Conclusion: TILs were variably correlated with better prognosis depending on their microanatomic location and subset of TILs in NPC patients. CD4+, intratumoral CD3+ and intratumoral CD8+ lymphocytes could predict favorable patient outcome which suggest that their role in mediating antitumor immune response could potentially be exploited in the treatment of NPC patients. Future large study on the prognostic value of microanatomic location of TILs is needed for confirmation.
Collapse
Affiliation(s)
| | - Yuxiang Cai
- Department of Pathology, 89674Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Guifang Yang
- Department of Pathology, 89674Zhongnan Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
37
|
Nishi M, Shimada M, Tokunaga T, Higashijima J, Yoshikawa K, Kashihara H, Takasu C, Ishikawa D, Wada Y, Eto S, Yoshimoto T. Lymphocyte to C-reactive protein ratio predicts long-term outcomes for patients with lower rectal cancer. World J Surg Oncol 2021; 19:201. [PMID: 34229704 PMCID: PMC8262012 DOI: 10.1186/s12957-021-02319-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/25/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUNDS The lymphocyte to C-reactive protein (CRP) ratio (LCR) is an indicator of systemic inflammation and host-tumor cell interactions. The aim of this study was to investigate the prognostic significance of LCR in lower rectal cancer patients who received preoperative chemo-radiotherapy (CRT). METHODS Forty-eight patients with lower rectal cancer who underwent CRT followed by curative surgery were enrolled in this study. Routine blood examinations were performed before and after CRT were used to calculate pre-CRT LCR and post-CRT LCR. The median LCR was used to stratify patients into low and high LCR groups for analysis. The correlation between pre- and post-CRT LCR and clinical outcomes was retrospectively investigated. RESULTS The pre-CRT LCR was significantly higher than the post-CRT LCR (11,765 and 6780, respectively, P < 0.05). The 5-year overall survival rate was significantly higher for patients with high post-CRT LCR compared with low post-CRT LCR (90.6% and 65.5%, respectively, P < 0.05). In univariate analysis, post-CRT LCR, post-CRT neutrophil to lymphocyte ratio, and fStage were significant prognostic factors for overall survival. In multivariate analysis, post-CRT LCR, but not other clinicopathological factors or prognostic indexes, was a significant prognostic factor for overall survival (P < 0.05). CONCLUSIONS Post-CRT LCR could be a prognostic biomarker for patients with lower rectal cancer.
Collapse
Affiliation(s)
- Masaaki Nishi
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
| | - Mistuo Shimada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takuya Tokunaga
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Jun Higashijima
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kozo Yoshikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hideya Kashihara
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Chie Takasu
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Daichi Ishikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yuma Wada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shohei Eto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Toshiaki Yoshimoto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| |
Collapse
|
|
38
|
Dai Y, Zhao W, Yue L, Dai X, Rong D, Wu F, Gu J, Qian X. Perspectives on Immunotherapy of Metastatic Colorectal Cancer. Front Oncol 2021; 11:659964. [PMID: 34178645 PMCID: PMC8219967 DOI: 10.3389/fonc.2021.659964] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/17/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer, especially liver metastasis, is still a challenge worldwide. Traditional treatment such as surgery, chemotherapy and radiotherapy have been difficult to be further advanced. We need to develop new treatment methods to further improve the poor prognosis of these patients. The emergence of immunotherapy has brought light to mCRC patients, especially those with dMMR. Based on several large trials, some drugs (pembrolizumab, nivolumab) have been approved by US Food and Drug Administration to treat the patients diagnosed with dMMR tumors. However, immunotherapy has reached a bottleneck for other MSS tumors, with low response rate and poor PFS and OS. Therefore, more clinical trials are underway toward mCRC patients, especially those with MSS. This review is intended to summarize the existing clinical trials to illustrate the development of immunotherapy in mCRC patients, and to provide a new thinking for the direction and experimental design of immunotherapy in the future.
Collapse
Affiliation(s)
- Yongjiu Dai
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Wenhu Zhao
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Lei Yue
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xinzheng Dai
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Dawei Rong
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jian Gu
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaofeng Qian
- Hepatobiliary/Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
39
|
Liang X, Yao S, Lu P, Ma Y, Xu H, Yin Z, Hu J, Liu Y, Wei S. The Prognostic Value of New Index (LANR) Composed of Pre-operative Lymphocytes, Albumin, and Neutrophils in Patients With Resectable Colorectal Cancer. Front Oncol 2021; 11:610264. [PMID: 34150609 PMCID: PMC8210780 DOI: 10.3389/fonc.2021.610264] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 02/08/2021] [Indexed: 12/31/2022] Open
Abstract
Background: Inflammatory factors and nutritional status are critical to the prognosis of colorectal cancer patients. This study aimed to investigate the prognostic value of the combination of preoperative lymphocytes, albumin, and neutrophils (LANR) in patients with resectable colorectal cancer. Methods: A total of 753 patients with pathologically diagnosed primary colorectal cancer were included in the study. The value of LANR was defined as follows: LANR, lymphocyte × albumin/neutrophil. The ROC curve, subgroup analysis and Cox proportional hazard regression analysis were used to assess the prognostic value of LANR in overall survival and progression-free survival. Results: The median age of the patients was 60 years (range 52–67 years). In overall survival, the area under the curve of LANR was 0.6276, and the HR (95% CI) was 0.551 (0.393–0.772). And in progression-free survival, the area under the curve of LANR was 0.5963, and the HR (95% CI) was 0.697 (0.550–0.884). The results indicate that preoperative LANR may be a reliable predictor of overall and progression-free survival in resectable colorectal cancer patients. Conclusions: LANR is an important prognostic indicator for patients with resectable colorectal cancer, and it can also provide a reference for clinicians and patients to choose a treatment plan.
Collapse
Affiliation(s)
- Xinjun Liang
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China.,Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Shuang Yao
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China.,Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Ping Lu
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China.,Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Yifei Ma
- Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China.,Department of Gastrointestinal Surgery, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hongli Xu
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China.,Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Zhucheng Yin
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China.,Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Junjie Hu
- Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China.,Department of Gastrointestinal Surgery, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yanyan Liu
- Division of Nephrology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shaozhong Wei
- Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, China.,Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China.,Department of Gastrointestinal Surgery, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
40
|
Harada Y, Kazama S, Morikawa T, Sonoda H, Ishi H, Emoto S, Murono K, Kaneko M, Sasaki K, Shuno Y, Nishikawa T, Tanaka T, Kawai K, Hata K, Nozawa H, Ushiku T, Tahara H, Ishihara S. Clinical significance of CD8 + and FoxP3 + tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy. Mol Clin Oncol 2021; 14:87. [PMID: 33767856 DOI: 10.3892/mco.2021.2249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 02/04/2021] [Indexed: 12/14/2022] Open
Abstract
Preoperative chemoradiotherapy (CRT) for rectal cancer contributes to tumor down-staging and decreases locoregional recurrence. However, each patient shows a significantly different response to CRT. Therefore, the identification of predictive factors to CRT response would be beneficial to avoid unnecessary treatment. Cancer immunity in patients has been suggested to play an important role in the eradication of the tumor by CRT. In the present study, the utility of CD8+ and forkhead box P3 (FoxP3)+ tumor-infiltrating lymphocytes (TILs) and the expression of a novel immuno-regulatory factor, lactadherin (MFG-E8), in predicting CRT effectiveness in patients with rectal cancer was examined. A total of 61 patients with rectal cancer, who underwent curative resection following CRT were included in the study. The numbers of CD8+ and FoxP3+ TILs in a biopsy taken before CRT and MFG-E8 expression level in the specimens obtained at the time of the surgery after CRT were examined using immunohistochemical staining, and their association with clinicopathological characteristics, including patient survival, was determined. The tumors with more CD8+ TILs in the biopsy samples before CRT showed a significantly more favorable CRT response. The patients with tumors and a higher number of CD8+ TILs before CRT also exhibited significantly longer disease-free and overall survival times. Higher MFG-E8 expression level in post-CRT specimens was significantly associated with favorable CRT response; however, no significant association was found with any other clinicopathological characteristics, including survival time. The number of CD8+ TILs before CRT was a valuable predictor for CRT response and was associated with favorable prognosis in patients with lower rectal cancer and who were treated with CRT. High MFG-E8 expression level after CRT was also associated with a favorable CRT response.
Collapse
Affiliation(s)
- Yuzo Harada
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shinsuke Kazama
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.,Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Teppei Morikawa
- Department of Pathology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan
| | - Hirofumi Sonoda
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hiroaki Ishi
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shigenobu Emoto
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Koji Murono
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Manabu Kaneko
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhito Sasaki
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yasutaka Shuno
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takeshi Nishikawa
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Toshiaki Tanaka
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazushige Kawai
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Keisuke Hata
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hiroaki Nozawa
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hideaki Tahara
- Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.,Department of Cancer Drug Discovery and Development Project, Osaka International Cancer Institute, Osaka 541-8567, Japan
| | - Soichiro Ishihara
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| |
Collapse
|
|
41
|
Yamakoshi Y, Tanaka H, Sakimura C, Mori T, Deguchi S, Yoshii M, Tamura T, Toyokawa T, Lee S, Muguruma K, Hirakawa K, Ohira M. Association between the preoperative neutrophil-to-lymphocyte ratio and tertiary lymphoid structures surrounding tumor in gastric cancer. Mol Clin Oncol 2021; 14:76. [PMID: 33680464 PMCID: PMC7922788 DOI: 10.3892/mco.2021.2238] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/12/2021] [Indexed: 11/24/2022] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with a poor prognosis in various types of cancer. We previously reported that an antitumor immune response was induced by tertiary lymphoid structures (TLSs) surrounding tumor, and increased TLS was an independent prognostic factor in patients with gastric cancer. The present study examined the stratification based on the correlation between the preoperative NLR and TLS density in gastric cancer. A total of 199 patients who underwent surgery for stage Ib-IV gastric cancer were included in the study. Receiver operating characteristic curve analysis was used to determine the appropriate cut-off values of the preoperative NLR and the TLS density. The prognostic factors were evaluated in a multivariate analysis. The median NLR was 2.18 (mean ± SD, 2.7±2.04). A total of 91 patients with an NLR ≥2.33 was classified into the high NLR group. The overall survival was significantly improved in patients with a low NLR than in those with a high NLR. Additionally, the low NLR group tended to have a high TLS density. The multivariate analysis indicated that the preoperative NLR and TLS density were independent risk factors. When the patients were classified into the high and low NLR and TLS groups and the survival rates were compared, the prognosis was significantly improved in the low NLR and high TLS group than in the other groups. The preoperative NLR may be associated with the presence of TLSs surrounding the tumor, and the combination of NLR and TLS may be useful for the stratification of patient prognosis. The present results suggested that the NLR and TLS density may be surrogate markers for immunotherapy against gastric cancer.
Collapse
Affiliation(s)
- Yoshihito Yamakoshi
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Hiroaki Tanaka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Chie Sakimura
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Takuya Mori
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Sota Deguchi
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Mami Yoshii
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Tatsuro Tamura
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shigeru Lee
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Kazuya Muguruma
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Kosei Hirakawa
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| |
Collapse
|
|
42
|
Ma XB, Xu YY, Zhu MX, Wang L. Prognostic Signatures Based on Thirteen Immune-Related Genes in Colorectal Cancer. Front Oncol 2021; 10:591739. [PMID: 33680920 PMCID: PMC7935549 DOI: 10.3389/fonc.2020.591739] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/29/2020] [Indexed: 12/20/2022] Open
Abstract
Background The immunosuppressive microenvironment is closely related to tumorigenesis and cancer development, including colorectal cancer (CRC). The aim of the current study was to identify new immune biomarkers for the diagnosis and treatment of CRC. Materials and Methods CRC data were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Sequences of immune-related genes (IRGs) were obtained from the ImmPort and InnateDB databases. Gene set enrichment analysis (GSEA) and transcription factor regulation analysis were used to explore potential mechanisms. An immune-related classifier for CRC prognosis was conducted using weighted gene co-expression network analysis (WGCNA), Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) analysis. ESTIMATE and CIBERSORT algorithms were used to explore the tumor microenvironment and immune infiltration in the high-risk CRC group and the low-risk CRC group. Results By analyzing the IRGs that were significantly associated with CRC in the module, a set of 13 genes (CXCL1, F2RL1, LTB4R, GPR44, ANGPTL5, BMP5, RETNLB, MC1R, PPARGC1A, PRKDC, CEBPB, SYP, and GAB1) related to the prognosis of CRC were identified. An IRG-based prognostic signature that can be used as an independent potentially prognostic indicator was generated. The ROC curve analysis showed acceptable discrimination with AUCs of 0.68, 0.68, and 0.74 at 1-, 3-, and 5- year follow-up respectively. The predictive performance was validated in the train set. The potential mechanisms and functions of prognostic IRGs were analyzed, i.e., NOD-like receptor signaling, and transforming growth factor beta (TGFβ) signaling. Besides, the stromal score and immune score were significantly different in high-risk group and low-risk group (p=4.6982e-07, p=0.0107). Besides, the proportions of resting memory CD4+ T cells was significantly higher in the high-risk groups. Conclusions The IRG-based classifier exhibited strong predictive capacity with regard to CRC. The survival difference between the high-risk and low-risk groups was associated with tumor microenvironment and immune infiltration of CRC. Innovative biomarkers for the prediction of CRC prognosis and response to immunological therapy were identified in the present study.
Collapse
Affiliation(s)
- Xiao-Bo Ma
- Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yuan-Yuan Xu
- Department of Day Surgery Centre, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Meng-Xuan Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Wang
- Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
43
|
Belnoue E, Leystra AA, Carboni S, Cooper HS, Macedo RT, Harvey KN, Colby KB, Campbell KS, Vanderveer LA, Clapper ML, Derouazi M. Novel Protein-Based Vaccine against Self-Antigen Reduces the Formation of Sporadic Colon Adenomas in Mice. Cancers (Basel) 2021; 13:cancers13040845. [PMID: 33671373 PMCID: PMC7923075 DOI: 10.3390/cancers13040845] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 02/11/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Colorectal cancer remains a leading cause of cancer-related mortality worldwide. However, high-risk populations with a genetic predisposition for colorectal cancer could benefit greatly from novel and efficacious immunopreventive strategies that afford long-lasting protection. The achaete-scute family bHLH transcription factor 2 (Ascl2) has been identified as a promising target for immunoprevention of colorectal cancer, based on its induction during the formation and progression of colorectal tumors and its minimal expression observed in healthy tissue. The goal of the present study was to determine the efficacy of a protein-based vaccine targeting Ascl2 in combination with an anti-PD-1 treatment in a spontaneous colorectal cancer mouse model. This novel vaccine strategy promotes potent tumor-specific immunity, and prevents the formation of colon adenomas in mice. The results demonstrate that Ascl2 is a promising target for immunoprevention for individuals at elevated risk of developing colorectal cancer. Abstract Novel immunopreventive strategies are emerging that show great promise for conferring long-term protection to individuals at high risk of developing colorectal cancer. The KISIMA vaccine platform utilizes a chimeric protein comprising: (1) a selected tumor antigen; (2) a cell-penetrating peptide to improve antigen delivery and epitope presentation, and (3) a TLR2/4 agonist to serve as a self-adjuvant. This study examines the ability of a KISIMA vaccine against achaete-scute family bHLH transcription factor 2 (Ascl2), an early colon cancer antigen, to reduce colon tumor formation by stimulating an anti-tumor immune response. Vaccine administrations were well-tolerated and led to circulating antibodies and antigen-specific T cells in a mouse model of colorectal cancer. To assess preventive efficacy, the vaccine was administered to mice either alone or in combination with the immune checkpoint inhibitor anti-PD-1. When delivered to animals prior to colon tumor formation, the combination strategy significantly reduced the development of colon microadenomas and adenomas, as compared to vehicle-treated controls. This response was accompanied by an increase in the intraepithelial density of CD3+ T lymphocytes. Together, these data indicate that the KISIMA-Ascl2 vaccine shows great potential to be a safe and potent immunopreventive intervention for individuals at high risk of developing colorectal cancer.
Collapse
Affiliation(s)
- Elodie Belnoue
- AMAL Therapeutics, Fondation pour Recherches Médicales, 64 avenue de la Roseraie, 1205 Geneva, Switzerland; (E.B.); (S.C.)
- Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany
| | - Alyssa A. Leystra
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
| | - Susanna Carboni
- AMAL Therapeutics, Fondation pour Recherches Médicales, 64 avenue de la Roseraie, 1205 Geneva, Switzerland; (E.B.); (S.C.)
- Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany
| | - Harry S. Cooper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
- Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA
| | - Rodrigo T. Macedo
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
| | - Kristen N. Harvey
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
| | - Kimberly B. Colby
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (K.B.C.); (K.S.C.)
| | - Kerry S. Campbell
- Blood Cell Development and Function Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (K.B.C.); (K.S.C.)
| | - Lisa A. Vanderveer
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
| | - Margie L. Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA; (A.A.L.); (H.S.C.); (R.T.M.); (K.N.H.); (L.A.V.)
- Correspondence: (M.L.C.); (M.D.)
| | - Madiha Derouazi
- AMAL Therapeutics, Fondation pour Recherches Médicales, 64 avenue de la Roseraie, 1205 Geneva, Switzerland; (E.B.); (S.C.)
- Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany
- Correspondence: (M.L.C.); (M.D.)
| |
Collapse
|
|
44
|
Jimenez-Rodriguez RM, Patil S, Keshinro A, Shia J, Vakiani E, Stadler Z, Segal NH, Yaeger R, Konishi T, Shimada Y, Widmar M, Wei I, Pappou E, Smith JJ, Nash G, Paty P, Garcia-Aguilar J, Weiser MR. Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer. Oncoimmunology 2020; 9:1841948. [PMID: 33235819 PMCID: PMC7671050 DOI: 10.1080/2162402x.2020.1841948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank P < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low (P = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.
Collapse
Affiliation(s)
| | - Sujata Patil
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ajaratu Keshinro
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neil H. Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tsuyoshi Konishi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Tokyo
| | - Yoshifumi Shimada
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Maria Widmar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Iris Wei
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emmanouil Pappou
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - J. Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Garrett Nash
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip Paty
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin R. Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
45
|
Clinical Characteristics of Colorectal Cancer Patients in terms of Selected Platelet Indices. DISEASE MARKERS 2020; 2020:6145604. [PMID: 33133303 PMCID: PMC7568811 DOI: 10.1155/2020/6145604] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 07/09/2020] [Accepted: 07/31/2020] [Indexed: 12/11/2022]
Abstract
Mounting evidence suggests that inflammation, immune response, and coagulation status determine many processes during the carcinogenesis pathway in colorectal cancer (CRC). Inflammation strongly promotes tumor formation, progression, and metastasis. The systemic inflammatory response (SIR) may be reflected by simple indicators evaluated on the basis of peripheral blood morphology parameters. The indices are easily obtained by the peripheral blood test and could be promising biomarkers for CRC. We present the results of the retrospective study evaluating the potential relation between the platelet indices (platelet count (PC), platelet-to-lymphocyte ratio (PLR), neutrophil platelet score (NPS), mean platelet volume (MPV), and MPV/PC ratio) and the clinicopathological features of CRC patients. The study included 247 patients (104 males and 143 females) aged 39-87 years with CRC stages II-IV. The complete blood counts with the automated differential counts were performed prior to the qualification to systemic treatment. High PC, high PLR, and NPS 0 were associated with older age and higher BMI of the patients. No link between the analyzed platelet indices and histological grade of the tumor, primary tumor location, and gender was noted. The patients aged ≥65 years were characterized by the higher MPV/PC ratio than the younger population. We observed a trend to the higher MPV/PC ratio among the patients with excessive body weight defined by BMI compared to BMI within normal limits. A higher frequency of PC > 400, NPS 1 and 2, and a trend to more frequent PLR ≥ 150 were observed in the subgroup with metastatic disease compared to individuals with CRC stages II and III. The presented results expand the knowledge on potential association between SIR parameters and other clinicopathological factors that should be considered during interpreting the prognostic and predictive value of the inflammation parameters.
Collapse
|
|
46
|
Pötzsch M, Berg E, Hummel M, Stein U, von Winterfeld M, Jöhrens K, Rau B, Daum S, Treese C. Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression. Oncoimmunology 2020; 9:1824632. [PMID: 33101772 PMCID: PMC7553533 DOI: 10.1080/2162402x.2020.1824632] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3+, CD4+, or CD8+ TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.
Collapse
Affiliation(s)
- M. Pötzsch
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
| | - E. Berg
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
| | - M. Hummel
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- 1.Institute for Pathology, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany
| | - U. Stein
- Experimental and Clinical Research Center, Charité - Universitätsmedizin, Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - M. von Winterfeld
- Institute of Pathology Heidelberg, University Hospital Heidelberg, Germany
| | - K. Jöhrens
- Institute of Pathology, University Carl Gustav Carus, Dresden, Germany
| | - B. Rau
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - S. Daum
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - C. Treese
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Berlin, Germany
- Experimental and Clinical Research Center, Charité - Universitätsmedizin, Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| |
Collapse
|
|
47
|
Chen X, Chen J, Feng Y, Guan W. Prognostic Value of SLC4A4 and its Correlation with Immune Infiltration in Colon Adenocarcinoma. Med Sci Monit 2020; 26:e925016. [PMID: 32949121 PMCID: PMC7526338 DOI: 10.12659/msm.925016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND SLC4A4 is differentially expressed in a variety of tumors, but its significance in colon adenocarcinoma has not been determined. MATERIAL AND METHODS Transcriptomes of two cohorts, GSE41258 and GSE32323, contained in The Cancer Genome Atlas (TCGA) were analysed to determine differences in SLC4A4 expression between tumor and normal tissue and their correlations with overall survival. The relationships between SLC4A4 expression and clinical characteristics were determined by COX regression analysis and logistic regression analysis, and correlations of SLC4A4 levels with tumor infiltrating immune cells (TIICs) and genes with high mutation frequency were evaluated by Pearson correlation analysis. Molecular functions and signaling pathways that might be affected by changes in SLC4A4 expression were determined by gene set enrichment analysis (GSEA). The overall distribution of TIICs was determined by two web servers: tumor immune estimation resource (TIMER) and CIBERSORT. RESULTS SLC4A4 expression was lower in colon adenocarcinoma than in normal colon tissue, suggesting that SLC4A4 was associated with poor prognosis. Reduced SLC4A4 expression was also associated with lymph node invasion and distant metastasis and was moderately correlated with increased expression of MUC4 and SMAD4, two genes with high mutation frequency in colon adenocarcinoma. GSEA indicated that changes in SLC4A4 expression affects several biological processes, including mismatch repair, base excision repair, and DNA replication. Eight TIICs in the tumor microenvironment differed significantly in groups with low and high expression of SLC4A4. CONCLUSIONS SLC4A4 may be a novel biomarker predicting prognosis in patients with colon adenocarcinoma. TIICs differed significantly in samples with higher and lower expression of SLC4A4.
Collapse
Affiliation(s)
- Xiaoli Chen
- Department of Pathology, The First People's Hospital of Nantong, Nantong, Jiangsu, China (mainland)
| | - Jianing Chen
- Medical School of Nantong University, Nantong, Jiangsu, China (mainland)
| | - Yan Feng
- Department of Pathology, The First People's Hospital of Nantong, Nantong, Jiangsu, China (mainland)
| | - Wei Guan
- Department of Radiation Oncology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (mainland)
| |
Collapse
|
|
48
|
González IA, Bauer PS, Liu J, Chatterjee D. Intraepithelial tumour infiltrating lymphocytes are associated with absence of tumour budding and immature/myxoid desmoplastic reaction, and with better recurrence-free survival in stages I-III colorectal cancer. Histopathology 2020; 78:252-264. [PMID: 32654226 DOI: 10.1111/his.14211] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/17/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022]
Abstract
AIMS Tumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, we evaluated their significance and relationship to each other and their cumulative effect on survival. METHODS AND RESULTS A total of 372 stages I-III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P = 0.0247), non-myxoid DR (P = 0.0004), poorly differentiated histology (P = 0.0015), absence of perineural invasion (P = 0.0367) and loss of mismatch repair proteins (P = 0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence-free survival (RFS) [hazard ratio (HR) = 2.191, 95% confidence interval (CI) = 1.232-3.895; and HR = 5.706, 95% CI = 3.632-8.964, respectively]. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P < 0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR = 0.214, 95% CI = 0.109-0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P < 0.0001). Cases with iTILs and a non-myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR = 0.113, 95% CI = 0.056-0.230). On multivariate cause-specific analysis, patients' age (P = 0.0045), iTILs (P = 0.0345), DR (P < 0.0001) and pTNM prognostic groups (P < 0.0001) were associated with RFS. CONCLUSIONS Our study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.
Collapse
Affiliation(s)
- I A González
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - P S Bauer
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - J Liu
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - D Chatterjee
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| |
Collapse
|
|
49
|
Yang Z, Zhang M, Peng R, Liu J, Wang F, Li Y, Zhao Q, Liu J. The prognostic and clinicopathological value of tumor-associated macrophages in patients with colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 2020; 35:1651-1661. [PMID: 32666290 DOI: 10.1007/s00384-020-03686-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE There is a growing literature on the significance of tumor-associated macrophages (TAMs) in colorectal cancer (CRC). However, the role of TAMs in predicting the prognosis of CRC remains controversial. The current study aims to determine the prognostic and clinicopathological value of different types and distribution of TAMs in CRC. METHODS A comprehensive literature search of PubMed, Embase, and Cochrane Library databases was conducted from the inception to 1 September 2019. The correlations of TAMs with overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and clinicopathological characteristics were analyzed. RESULTS A total of 5,575 patients from 29 studies were included in this meta-analysis. The pooled hazard ratios (HRs) indicated that high density of pan-macrophages in tumor invasive margin (IM) was associated with better OS (HR = 0.57, 95%CI = 0.38-0.85), DFS (HR = 0.32, 95%CI = 0.19-0.52), and CSS (HR = 0.56, 95%CI = 0.41-0.77). Moreover, the high density of pan-macrophages in tumor center (TC) was correlated with better DFS (HR = 0.66, 95%CI = 0.45-0.96). However, high expression of M2 macrophages in TC was associated with poor DFS (HR = 2.42, 95%CI = 1.45-4.07) and CSS (HR = 1.74, 95%CI = 1.24-2.44). High M2 macrophages density in IM was also associated with short DFS (HR = 2.81, 95%CI = 1.65-4.77). In addition, the results showed that high density of pan-macrophages in IM was associated with no tumor metastasis, while high M2 macrophages density in TC was correlated with poor tumor differentiation. CONCLUSION High Pan-TAMs density in IM has a positive effect on the prognosis of CRC patients, while high density M2 macrophage infiltration in TC is a strong indicator of poor prognosis.
Collapse
Affiliation(s)
- Zhenwei Yang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Ruyi Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jialong Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Yizhang Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China.
| |
Collapse
|
|
50
|
Assessment of Tumor-infiltrating Lymphocytes Using International TILs Working Group (ITWG) System Is a Strong Predictor of Overall Survival in Colorectal Carcinoma: A Study of 1034 Patients. Am J Surg Pathol 2020; 44:536-544. [PMID: 31743129 DOI: 10.1097/pas.0000000000001409] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The presence of increased tumor-infiltrating lymphocytes (TILs) is established as a positive prognostic factor in many malignancies including colorectal carcinoma (CRC). However, multiple different approaches have been used to assess TILs. In 2014, the International TILs Working Group (ITWG) proposed a standardized methodology for evaluating TILs, initially in the context of breast cancer, but subsequently expanded to other malignancies. To date, the efficacy of the ITWG system has not been investigated in a large cohort of all-stage CRC. We, therefore, sought to validate this system in CRC. We used the ITWG system to assess the density of stromal TILs in an unselected cohort of 1034 CRC patients undergoing primary tumor resection at our institution. The percentage TILs' score was categorized into 3 groups: low (0% to 10%), intermediate (15% to 50%), and high (55% to 100%). The mean survival was 53, 67, and 75 months, respectively (P=0.0001). This survival benefit remained statistically significant in multivariate analyses (P=0.0001) and subgroup analyses of mismatch repair-proficient CRCs (P=0.0001), mismatch repair-deficient CRCs (P=0.031), BRAFV600E-mutant CRCs (P=0.0001), and BRAF wild-type CRCs (P=0.001). The predictive value of TILs assessed using the ITWG system was superior to the assessment of intraepithelial lymphocyte performed prospectively using a standard system requiring ≥5 lymphocytes per high-powered field in direct contact with tumor cells or between tumor clusters. We conclude that the ITWG system for assessing TILs is a powerful predictor of all-cause survival in CRC independent of many prognostic factors and superior to the assessment of intraepithelial lymphocytes using a traditional system.
Collapse
|