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Cotan HT, Emilescu RA, Iaciu CI, Orlov-Slavu CM, Olaru MC, Popa AM, Jinga M, Nitipir C, Schreiner OD, Ciobanu RC. Prognostic and Predictive Determinants of Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:3928. [PMID: 39682117 DOI: 10.3390/cancers16233928] [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: 11/06/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes. This systematic review aims to comprehensively evaluate prognostic and predictive determinants in CRC, encompassing both traditional and emerging biomarkers. A systematic search of major electronic databases was conducted to identify relevant studies published from 1995 up to 2024. Eligible articles were critically appraised, and data extraction was performed according to predefined criteria. The prognostic determinants examined included clinicopathological features such as tumor stage, grade, and lymph node involvement, as well as molecular biomarkers including RAS, BRAF, and MSI status. Predictive determinants encompassed biomarkers influencing response to targeted therapies and immunotherapy, such as HER2 and Immunoscore. The review also explores novel prognostic and predictive markers, including tumor microenvironment characteristics and liquid biopsy-based biomarkers. Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes.
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Affiliation(s)
- Horia T Cotan
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Radu A Emilescu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristian I Iaciu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristina M Orlov-Slavu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mihaela C Olaru
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Ana M Popa
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mariana Jinga
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cornelia Nitipir
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Oliver Daniel Schreiner
- Regional Institute of Oncology Iasi, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania
- Department 3-Medical Sciences, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
| | - Romeo Cristian Ciobanu
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
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Azizi M, Mokhtari Z, Tavana S, Bemani P, Heidari Z, Ghazavi R, Rezaei M. A Comprehensive Study on the Prognostic Value and Clinicopathological Significance of Different Immune Checkpoints in Patients With Colorectal Cancer: A Systematic Review and Meta-Analysis. CURRENT THERAPEUTIC RESEARCH 2024; 101:100760. [PMID: 39434898 PMCID: PMC11492099 DOI: 10.1016/j.curtheres.2024.100760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 08/30/2024] [Indexed: 10/23/2024]
Abstract
Background The prognostic significance of immune checkpoint expression in the tumor microenvironment has been widely investigated in colorectal cancers. However, the results of these studies are inconsistent and limited to some immune checkpoints. Objective The study aimed to investigate the correlation between different immune checkpoint expression and clinicopathological features and prognostic parameters. Methods We conducted a systematic review and meta-analysis of the published literature in PubMed, Web of Science-Core Collection, Scopus, Embase, and Cochrane databases to summarize the association between various immune checkpoints expression on both tumor cells and immune cells with clinicopathological features and prognostic parameters in patients with colorectal cancer. Results One hundred four studies incorporating 22,939 patients were included in our meta-analysis. Our results showed that among the B7 family, the high expression of B7H3, B7H4, PD-1, and PD-L1 on tumor cells and tumor tissue was significantly associated with higher T stage, advanced tumor, node, metastasis (TNM) stage, presence of vascular invasion, and lymphatic invasion. In addition, patients with high expression of B7H3, B7H4, PD-1, PD-L1, and PD-L2 were associated with shorter overall survival. High expression of PD-1 and PD-L1 in immune cells correlated with the absence of lymph node metastasis, lower TNM stage, early T stage, poor overall survival, and disease-free survival, respectively. Moreover, we found significant positive correlations between CD70 and Galectin-3 expression with advanced T stage. HLA-II overexpression was correlated with the absence of lymph node metastasis (odds ratio = 0.21, 95% CI = 0.11-0.38, P < 0.001) and early TNM stage (odds ratio = 0.35, 95% CI = 0.26-0.47, P < 0.001). Conclusions Overexpression of B7H3, B7H4, PD-1, PD-L1, PD-L2, CD70, and Galectin-3 on tumors is significantly associated with unfavorable clinicopathological characteristics and poor prognostic factors. Hence, these immune checkpoints can serve as predictive biomarkers for prognosis and the clinicopathological features of colorectal cancer because this is essential to identify patients suitable for anticancer therapy with immune checkpoint inhibitors.
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Affiliation(s)
- Mahdieh Azizi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Mokhtari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Tavana
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Bemani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Heidari
- Department of Biostatistics and Epidemiology, Faculty of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roghayeh Ghazavi
- Department of Knowledge and Information Science, Faculty of Education and Psychology, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Marzieh Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Yang C, Zhao L, Lin Y, Wang S, Ye Y, Shen Z. Improving the efficiency of immune checkpoint inhibitors for metastatic pMMR/MSS colorectal cancer: Options and strategies. Crit Rev Oncol Hematol 2024; 200:104204. [PMID: 37984588 DOI: 10.1016/j.critrevonc.2023.104204] [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: 07/13/2023] [Revised: 10/24/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and been extensively used for patients with metastastic colorectal cancer (mCRC), especially those harboring deficient mismatch repair/ microsatellite instability (dMMR/MSI). However, the majority of mCRC are classified as proficient mismatch repair/microsatellite stability(pMMR/MSS) type characterized by a cold immune microenvironment, rendering them generally unresponsive to ICIs. How to improve the efficacy of ICIs for these patients is an important issue to be solved. On the one hand, it is urgent to discover the predictive biomarkers and clinical characteristics associated with effectiveness and expand the subset of pMMR/MSS mCRC patients who benefit from ICIs. Additionally, combined strategies are being explored to modulate the immune microenvironment of pMMR/MSS CRC and facilitate the conversion of cold tumors into hot tumors. In this review, we have focused on the recent advancements in the predictive biomarkers and combination therapeutic strategies with ICIs for pMMR/MSS mCRC.
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Affiliation(s)
- Changjiang Yang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Long Zhao
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Yilin Lin
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Shan Wang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Yingjiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China
| | - Zhanlong Shen
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, PR China.
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González A, Fullaondo A, Odriozola A. Microbiota-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:123-205. [PMID: 39396836 DOI: 10.1016/bs.adgen.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Liu W, Tang T, Feng J, Wang C, Lin L, Wang S, Zeng K, Zou R, Yang Z, Zhao Y. Knowledge graph construction based on granulosa cells transcriptome from polycystic ovary syndrome with normoandrogen and hyperandrogen. J Ovarian Res 2024; 17:38. [PMID: 38347589 PMCID: PMC10860235 DOI: 10.1186/s13048-024-01361-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 01/27/2024] [Indexed: 02/15/2024] Open
Abstract
PCOS is a widespread disease that primarily caused in-pregnancy in pregnant-age women. Normoandrogen (NA) and Hyperandrogen (HA) PCOS are distinct subtypes of PCOS, while bio-markers and expression patterns for NA PCOS and HA PCOS have not been disclosed. We performed microarray analysis on granusola cells from NA PCOS, HA PCOS and normal tissue from 12 individuals. Afterwards, microarray data were processed and specific genes for NA PCOS and HA PCOS were identified. Further functional analysis selected IL6R and CD274 as new NA PCOS functional markers, and meanwhile selected CASR as new HA PCOS functional marker. IL6R, CD274 and CASR were afterwards experimentally validated on mRNA and protein level. Subsequent causal relationship analysis based on Apriori Rules Algorithm and co-occurrence methods identified classification markers for NA PCOS and HA PCOS. According to classification markers, downloaded transcriptome datasets were merged with our microarray data. Based on merged data, causal knowledge graph was constructed for NA PCOS or HA PCOS and female infertility on NA PCOS and HA PCOS. Gene-drug interaction analysis was then performed and drugs for HA PCOS and NA PCOS were predicted. Our work was among the first to indicate the NA PCOS and HA PCOS functional and classification markers and using markers to construct knowledge graphs and afterwards predict drugs for NA PCOS and HA PCOS based on transcriptome data. Thus, our study possessed biological and clinical value on further understanding the inner mechanism on the difference between NA PCOS and HA PCOS.
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Affiliation(s)
- Wensu Liu
- Health Sciences Institute, China Medical University, Shenyang, 110122, Liaoning Province, China
| | - Tianyu Tang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Jianwei Feng
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
| | - Chunyu Wang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Lin Lin
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Shengli Wang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Kai Zeng
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Renlong Zou
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China
| | - Zeyu Yang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China.
| | - Yue Zhao
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China.
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Xu JL, Yang MX, Lan HR, Jin KT. Could immunoscore improve the prognostic and therapeutic management in patients with solid tumors? Int Immunopharmacol 2023; 124:110981. [PMID: 37769534 DOI: 10.1016/j.intimp.2023.110981] [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: 08/12/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 10/03/2023]
Abstract
The Immunoscore (ISc) is an emerging immune-based scoring system that has shown potential in improving the prognostic and therapeutic management of patients with solid tumors. The ISc evaluates the immune infiltrate within the tumor microenvironment (TME) and has demonstrated superior predictive ability compared to traditional histopathological parameters. It has been particularly promising in colorectal, lung, breast, and melanoma cancers. This review summarizes the clinical evidence supporting the prognostic value of the ISc and explores its potential in guiding therapeutic decisions, such as the selection of adjuvant therapies and recognizing patients likely to profit from immune checkpoint inhibitors (ICIs). The challenges and future directions of ISc implementation are also discussed, including standardization and integration into routine clinical practice.
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Affiliation(s)
- Jing-Lun Xu
- Department of Dermatology, Jinhua Fifth Hospital, Jinhua, Zhejiang 321000, China
| | - Meng-Xiang Yang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Huan-Rong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, China.
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China.
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Park J, Kim JC, Lee M, Lee J, Kim YN, Lee YJ, Kim S, Kim SW, Park SH, Lee JY. Frequency of peripheral PD-1 +regulatory T cells is associated with treatment responses to PARP inhibitor maintenance in patients with epithelial ovarian cancer. Br J Cancer 2023; 129:1841-1851. [PMID: 37821637 PMCID: PMC10667217 DOI: 10.1038/s41416-023-02455-z] [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: 01/16/2023] [Revised: 09/13/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis) are becoming the standard of care for epithelial ovarian cancer (EOC). Recently, clinical trials of triple maintenance therapy (PARPi+anti-angiogenic agent+anti-PD-1/L1) are actively ongoing. Here, we investigated the immunological effects of PARPi or triple maintenance therapy on T cells and their impact on clinical responses. METHODS We collected serial blood from EOC patients receiving PARPi therapy (cohort 1: PARPi, n = 49; cohort 2: olaparib+bevacizumab+pembrolizumab, n = 31). Peripheral T cells were analyzed using flow cytometry and compared according to the PARPi response. Progression-free survival (PFS) was assessed according to prognostic biomarkers identified in a comparative analysis. RESULTS Regulatory T cells (Tregs) were suppressed by PARPi therapy, whereas PD-1 was not significantly changed. Short PFS group exhibited a higher percentage of baseline PD-1+Tregs than long PFS group, and the patients with high percentage of PD-1+Tregs before treatment showed poor PFS in cohort 1. However, the expression of PD-1 on Tregs significantly decreased after receiving triple maintenance therapy, and the reduction in PD-1+Tregs was associated with superior PFS in cohort 2 (P = 0.0078). CONCLUSION PARPi suppresses Tregs, but does not affect PD-1 expression. Adding anti-PD-1 to PARPi decreases PD-1+Tregs, which have negative prognostic value for PARPi monotherapy.
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Affiliation(s)
- Junsik Park
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Chul Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Miran Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - JooHyang Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoo-Na Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Jae Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sunghoon Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Wun Kim
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Su-Hyung Park
- Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Jung-Yun Lee
- Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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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.
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Kanno H, Hisaka T, Fujiyoshi K, Akiba J, Hashimoto K, Fujita F, Akagi Y. Prognostic Significance of the Histopathological Growth Pattern and Tumor-Infiltrating Lymphocytes in Stratifying Survival After Hepatectomy for Colorectal Liver Metastases. Ann Surg Oncol 2022; 30:3139-3147. [PMID: 36520232 DOI: 10.1245/s10434-022-12905-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND A histopathological growth pattern (HGP) occurs at the interface between tumor cells and the surrounding liver parenchyma. Desmoplastic HGP (dHGP) is associated with a favorable prognosis and shows denser infiltration of lymphocytes than other HGPs. Tumor-infiltrating lymphocytes (TILs) exert antitumor immunity, nonetheless, their prognostic significance in patients with dHGP is unknown. This study aimed to identify the prognostic significance of HGP and TILs in colorectal liver metastasis (CRLM). METHODS The study analyzed 140 patients who underwent hepatectomy for CRLM. Depending on the type of HGP and TIL, the patients were categorized into four groups (dHGP/high TIL, dHGP/low TIL, non-dHGP/high TIL, and non-dHGP/low TIL) for a comparison of their recurrence-free survival (RFS) and overall survival (OS). Uni- and multivariate analyses were performed using a Cox proportional hazards model. RESULTS The RFS and OS curves differed significantly between the groups. The multivariate analysis showed that a combination of HGP and TIL could stratify the recurrence and survival outcomes. CONCLUSION This study indicated that a combination of HGP and TIL can stratify the risk of survival after hepatectomy in patients with CRLM.
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Affiliation(s)
- Hiroki Kanno
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
| | - Toru Hisaka
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Kenji Fujiyoshi
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Jun Akiba
- Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
| | - Kazuaki Hashimoto
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Fumihiko Fujita
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Yoshito Akagi
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
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11
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Programmed death-ligand 1 expression in the immune compartment of colon carcinoma. Mod Pathol 2022; 35:1740-1748. [PMID: 35773332 DOI: 10.1038/s41379-022-01128-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 11/08/2022]
Abstract
Programmed cell death ligand 1 (PD-L1) on tumor cells is a significant prognostic biomarker for a number of malignancies, although less is known about the significance of PD-L1 positive immune cells in colon carcinoma. The purpose of this study is to evaluate the role of PD-L1 in a large cohort of colon carcinomas to identify patterns of PD-L1 expression in the tumor microenvironment and its correlation with other key immune subsets to better understand the impact of these immune cells. We assessed 1218 colon carcinomas on representative tissue microarray sections, gathered relevant clinicopathologic information, and performed immunohistochemical staining for mismatch repair proteins, CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. We then performed automated quantification; manual quantification was used for PD-L1 tumor cells and immune cells. Dual PD-L1/PU.1 immunostain was also performed. The majority of PD-L1 positive cells expressed PU.1 thus representing tumor-associated macrophages. Based on the median number of PD-L1 positive immune cells (7.6/mm2), we classified tumors into two classes: (1) PD-L1 immune cell low and (2) PD-L1 immune cell high. PD-L1 immune cell high colon carcinomas showed favorable prognostic pathologic features including less frequent extramural venous invasion (p = 0.0001) and lower AJCC stage (p = 0.0001); they were also more commonly associated with deficient mismatch repair (dMMR) (p = 0.0001) and BRAF V600E reactivity. PD-LI immune cell high tumors were associated with high CD8, CD163, and FoxP3 positive cells (p = 0.0001, respectively). PD-L1 immune cell high and LAG3 high colon carcinomas were associated with improved disease-specific survival (p = 0.0001 and 0.001, respectively). PD-L1 expression on tumor cells was not associated with disease-specific survival. On multivariate analysis of chemotherapy naïve stage 2 colon carcinomas, only extramural venous invasion (p = 0.002), perineural invasion (p = 0.001) and PD-L1 immune cell expression (p = 0.032) correlated with disease-specific survival. Resected colonic carcinomas with high expression of PD-L1 and LAG3 proteins on immune cells were associated with improved prognosis in colon carcinoma. The mechanism underlying the improved prognosis of colon carcinomas bearing high numbers of immunoregulatory cells needs further investigation.
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12
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Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat Med 2022; 28:1872-1882. [PMID: 36038629 PMCID: PMC9499856 DOI: 10.1038/s41591-022-01916-x] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/27/2022] [Indexed: 12/12/2022]
Abstract
Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel–related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL. Analysis of tumor biopsies from the pivotal phase 1/2 ZUMA-1 trial identifies pre-treatment T cell–related characteristics that are associated with clinical response and neurologic toxicity after anti-CD19 CAR T cell therapy in patients with large B cell lymphoma.
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13
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Sonal S, Deshpande V, Ting DT, Cusack JC, Parikh AR, Neyaz A, Pankaj A, Taylor MS, Dinaux AM, Leijssen LGJ, Boudreau C, Locascio JJ, Kunitake H, Goldstone RN, Bordeianou LG, Cauley CE, Ricciardi R, Berger DL. Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma. Ann Surg Oncol 2022; 29:7372-7382. [PMID: 35917013 DOI: 10.1245/s10434-022-12212-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.
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Affiliation(s)
- Swati Sonal
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - David T Ting
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - James C Cusack
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Aparna R Parikh
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - Azfar Neyaz
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Amaya Pankaj
- Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA, USA
| | - Martin S Taylor
- Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Anne M Dinaux
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Chirurgie, Albert Schweitzer Ziekenhuis, Dordrecht, The Netherlands
| | - Lieve G J Leijssen
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.,Department of Gastroenterology and Hepatology, Amsterdams University Medical Centers, Amsterdam, The Netherlands
| | - Chloe Boudreau
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Joseph J Locascio
- Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Hiroko Kunitake
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Robert N Goldstone
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Liliana G Bordeianou
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Christy E Cauley
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - Rocco Ricciardi
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA
| | - David L Berger
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.
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14
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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15
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Du F, Liu Y. Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer. J Clin Lab Anal 2022; 36:e24141. [PMID: 34817097 PMCID: PMC8761449 DOI: 10.1002/jcla.24141] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/12/2021] [Accepted: 11/13/2021] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non-small-cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d-MMR), microsatellite instability-high (MSI-H), tumor mutational burden (TMB), programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in-depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.
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Affiliation(s)
- Fenqi Du
- Department of Colorectal SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Yanlong Liu
- Department of Colorectal SurgeryHarbin Medical University Cancer HospitalHarbinChina
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16
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Zhulai G, Oleinik E. Targeting regulatory T cells in anti-PD-1/PD-L1 cancer immunotherapy. Scand J Immunol 2021; 95:e13129. [PMID: 34936125 DOI: 10.1111/sji.13129] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/24/2021] [Accepted: 12/15/2021] [Indexed: 11/29/2022]
Abstract
The programmed death (PD)-1/PD-ligand (PD-L) pathway and regulatory T cells (Tregs) are essential for the maintenance of immune tolerance. Their activation in the tumor microenvironment contributes to the evasion of the transformed cells from the immune surveillance and the suppression of an antitumor immune response. Therefore, PD-1/PD-L1 and Tregs are important targets for cancer immunotherapy. Our review focuses on the current role of the PD-1/PD-L1 axis in Treg development and function in the tumor microenvironment. We also discuss combination therapy with PD-1/PD-L1 inhibitors and Treg-modulating agents affecting the adenosinergic pathway, TGF-β signaling, immune checkpoints, and other approaches to downregulation of Tregs.
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Affiliation(s)
- Galina Zhulai
- Institute of Biology, Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Russian Federation
| | - Eugenia Oleinik
- Institute of Biology, Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Russian Federation
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17
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Chen K, Collins G, Wang H, Toh JWT. Pathological Features and Prognostication in Colorectal Cancer. Curr Oncol 2021; 28:5356-5383. [PMID: 34940086 PMCID: PMC8700531 DOI: 10.3390/curroncol28060447] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
The prognostication of colorectal cancer (CRC) has traditionally relied on staging as defined by the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM staging classifications. However, clinically, there appears to be differences in survival patterns independent of stage, suggesting a complex interaction of stage, pathological features, and biomarkers playing a role in guiding prognosis, risk stratification, and guiding neoadjuvant and adjuvant therapies. Histological features such as tumour budding, perineural invasion, apical lymph node involvement, lymph node yield, lymph node ratio, and molecular features such as MSI, KRAS, BRAF, and CDX2 may assist in prognostication and optimising adjuvant treatment. This study provides a comprehensive review of the pathological features and biomarkers that are important in the prognostication and treatment of CRC. We review the importance of pathological features and biomarkers that may be important in colorectal cancer based on the current evidence in the literature.
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Affiliation(s)
- Kabytto Chen
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - Geoffrey Collins
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - Henry Wang
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - James Wei Tatt Toh
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
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18
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Zhou C, Cheng X, Tu S. Current status and future perspective of immune checkpoint inhibitors in colorectal cancer. Cancer Lett 2021; 521:119-129. [PMID: 34464671 DOI: 10.1016/j.canlet.2021.07.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/23/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022]
Abstract
Immune checkpoint inhibitors (ICIs), as a subverter of immunotherapy in oncology, are changing all aspects of therapy for malignant tumors, especially their remarkable effects on melanoma and non-small cell lung cancer (NSCLC). For colorectal cancer (CRC), only a small number of patients with high immunogenicity (microsatellite instability-high/mismatch-repair deficient (MSI-H/dMMR)) benefit greatly from ICIs treatment, and most CRC patients with low immunogenicity (microsatellite instability-low/mismatch-repair proficient (MSI-L/pMMR)) do not. Currently, numerous clinical trials are ongoing to improve CRC patients' response to ICIs immunotherapy through better patient selection and novel combination strategies. Thus, this review discusses the current status and latest progress of ICIs treatment in CRC. We expect that these studies can change the pattern of CRC immunotherapy in the future.
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Affiliation(s)
- Cong Zhou
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Xiaojiao Cheng
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; State Key Laboratory of Oncogenesis and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuiping Tu
- Department of Oncology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; State Key Laboratory of Oncogenesis and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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19
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Gu Q, Li J, Chen Z, Zhang J, Shen H, Miao X, Zhou Y, Xu X, He S. Expression and Prognostic Significance of PD-L2 in Diffuse Large B-Cell Lymphoma. Front Oncol 2021; 11:664032. [PMID: 34178648 PMCID: PMC8222690 DOI: 10.3389/fonc.2021.664032] [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: 02/04/2021] [Accepted: 05/05/2021] [Indexed: 01/22/2023] Open
Abstract
Recent studies suggest that programmed death ligand-2 (PD-L2) constitutes an important antitumor immune response. Here, we investigated the relationship between PD-L2 expression and clinicopathological features in diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry showed that positive expression of PD-L2 was observed in 45 of 181 newly diagnosed patients, including 14 cases with expression exclusively on tumor cells (TCs) and 31 cases with the expression on both TCs and immune cells (ICs) in the tumor microenvironment (TME). In 21 recurrent patients, positive expression of PD-L2 was present in six cases, including two cases with expression exclusively on TCs, and four cases with the expression on both TCs and ICs in the TME. Patients with PD-L2 tumor proportion score (TPS) ≥1% exhibited a better ECOG performance status (PS) (ECOG PS score <2, P = 0.041), lower international prognostic index (IPI) score (P < 0.001), and early Ann Arbor stage (Ann Arbor stage I or II, P = 0.010). Similarly, patients with PD-L2 immune proportion score (IPS) ≥1% also exhibited a better ECOG PS (ECOG PS score < 2, P = 0.006) and lower IPI score (P = 0.001). Survival analysis showed that patients with PD-L2 TPS ≥1% exhibited prolonged overall survival (OS) and progression-free survival (PFS). However, survival analysis showed no prognostic significance based on expression of PD-L2 on ICs in the TME. TC PD-L2 expression was significantly associated with OS (P = 0.041) and PFS (P = 0.001). In the multivariate analysis, TC PD-L2 expression was an independent prognostic risk factor for PFS (P = 0.013), but not for OS (P = 0.249). Furthermore, we found that higher TC and IC PD-L2 expression was associated with higher objective response rate (ORR). Moreover, we demonstrated that the expression level of PD-L2 was positively correlated with the expression status of M1 macrophage markers CD86. Our findings highlight PD-L2 as a promising therapeutic target in DLBCL.
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Affiliation(s)
- Qianhui Gu
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China.,Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China.,Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Jing Li
- Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Zhuolin Chen
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Jie Zhang
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Hui Shen
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Xiaobing Miao
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Ying Zhou
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Xiaohong Xu
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
| | - Song He
- Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China
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20
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Wang S, Yuan B, Wang Y, Li M, Liu X, Cao J, Li C, Hu J. Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis. Int J Colorectal Dis 2021; 36:117-130. [PMID: 32910207 PMCID: PMC7782388 DOI: 10.1007/s00384-020-03734-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To systematically evaluate the correlation between PD-L1 expression and clinicopathological features and prognosis of colorectal cancer (CRC). METHODS Seven databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) were searched through May 2020. Risk of bias and quality of evidence were assessed by using the Newcastle-Ottawa scale (NOS), and meta-analysis was carried out by using the Review Manager 5.3 software on the studies with the quality evaluation scores ≥ 6. Meta-regression analysis was used to determine the independent role of PD-L1 expression on CRC prognosis after adjusting clinicopathological features and treatment methods. RESULTS A total of 8823 CRC patients in 32 eligible studies. PD-L1 expression was correlated with lymphatic metastasis (yes/no; OR = 1.24, 95% CI (1.11, 1.38)), diameter of tumor (≥ 5 cm/< 5 cm; OR = 1.34, 95% CI (1.06, 1.70)), differentiation (high-middle/low; OR = 0.68, 95% CI (0.53, 0.87)), and vascular invasion (yes/no; OR = 0.80, 95% CI (0.69, 0.92)). PD-L1 expression shortened the overall survival (hazard ratio (HR) = 1.93, 95% CI (1.66, 2.25)), disease-free survival (HR = 1.76, 95% CI (1.50, 2.07)), and progression-free survival (HR = 1.93, 95% CI (1.55, 2.41)). Meta-regression showed that PD-L1 expression played a significant role on poor CRC OS (HR = 1.95, 95% CI (1.92, 3.98)) and disease-free survival (HR = 2.14, 95% CI (0.73, 4.52)). CONCLUSION PD-L1 expression independently predicted a poor prognosis of CRC.
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Affiliation(s)
- Shuxia Wang
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Bo Yuan
- Basic Medical School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Yun Wang
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Mingyang Li
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Xibo Liu
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Jing Cao
- Public Health School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Changtian Li
- Basic Medical School, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Jihong Hu
- Center of Research and Experiment, Gansu University of Chinese Medicine, Lanzhou, 730000, China.
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21
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Alexander PG, McMillan DC, Park JH. A meta-analysis of CD274 (PD-L1) assessment and prognosis in colorectal cancer and its role in predicting response to anti-PD-1 therapy. Crit Rev Oncol Hematol 2020; 157:103147. [PMID: 33278675 DOI: 10.1016/j.critrevonc.2020.103147] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 10/24/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND PD-1 checkpoint inhibitors are novel therapeutic agents in colorectal cancer (CRC). Immunohistochemical staining for CD274 assessment is standardised in upper GI cancer, but not in CRC. METHODS Methodologies of relevant studies were scrutinized and meta-analysis of survival and CD274/PDCD1 performed. Furthermore, anti-PD-1 therapy clinical trial results in CRC were assessed with particular emphasis on CD274 assessment. RESULTS 24 studies were included. CD274 on immune cells was associated with good prognosis. CD274 on tumour cells has heterogenous outcomes and does not meet requirements of a prognostic marker. As a marker of response to anti-PD-1 therapy, CD274 assessment is not standardised in CRC. CONCLUSION CD274 does not appear useful as a prognostic marker. As a marker of response to anti-PD-1 therapy, assessment methodology requires standardisation. As the Combined Positive Score (CPS) is used in upper GI cancer, this seems a logical method to adopt. Thresholds for CRC remain to be determined.
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Affiliation(s)
| | | | - James H Park
- School of Medicine, University of Glasgow, Glasgow, United Kingdom
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22
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Chakrabarti S, Peterson CY, Sriram D, Mahipal A. Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions. World J Gastrointest Oncol 2020; 12:808-832. [PMID: 32879661 PMCID: PMC7443846 DOI: 10.4251/wjgo.v12.i8.808] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/16/2020] [Accepted: 08/01/2020] [Indexed: 02/05/2023] Open
Abstract
Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.
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Affiliation(s)
- Sakti Chakrabarti
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Carrie Y Peterson
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Deepika Sriram
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
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Zhang X, Yang J, Du L, Zhou Y, Li K. The prognostic value of Immunoscore in patients with cancer: A pooled analysis of 10,328 patients. Int J Biol Markers 2020; 35:3-13. [PMID: 32538254 DOI: 10.1177/1724600820927409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Over the past decade, some publications have reported that Immunoscore was associated with the prognosis of several cancers. To better understand this issue, we conducted this pooled analysis. METHODS We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from their inceptions to 15 May 2019 to identify relevant articles. The pooled hazard ratio (HR) and 95% confidence interval (CI) was estimated for overall survival, disease-free survival, and disease-specific survival. RESULTS A total of 26 cohort studies with 10,328 patients involving eight cancer specialties were evaluated mainly by the consensus Immunoscore. The pooled analysis indicated that a lower Immunoscore was associated with a poor overall survival (HR 2.23, 95% CI 1.58, 2.70), disease-free survival (HR 2.40, 95% CI 1.96, 2.49), and disease-specific survival (HR 2.81, 95% CI 2.10, 3.77) for all cancers. The same convincing results were found in colorectal cancer, gastric cancer, and non-small cell lung cancer (especially the consensus Immunoscore for colon cancer). In five other types of cancer the results were similar, but the sample sizes were limited. CONCLUSIONS These findings support that Immunoscore is significantly associated with the prognosis of patients with cancer. It provides a reliable estimate of the risk of recurrence in patients with colon cancer. However, more high-quality studies are necessary to assess the prognostic value of Immunoscore in non-colon cancers.
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Affiliation(s)
- Xingxia Zhang
- West China School of Nursing / West China Hospital Gastrointestinal Surgery Department, Sichuan University
| | - Jie Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Liang Du
- Chinese Evidence-based Medicine/Cochrane Center, Chengdu, China
| | - Yong Zhou
- West China School of Nursing / West China Hospital Gastrointestinal Surgery Department, Sichuan University
| | - Ka Li
- West China School of Nursing / West China Hospital Gastrointestinal Surgery Department, Sichuan University
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24
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Guo L, Wang C, Qiu X, Pu X, Chang P. Colorectal Cancer Immune Infiltrates: Significance in Patient Prognosis and Immunotherapeutic Efficacy. Front Immunol 2020; 11:1052. [PMID: 32547556 PMCID: PMC7270196 DOI: 10.3389/fimmu.2020.01052] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 04/30/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer occurrence and progression involve multiple aspects of host immune deficiencies. In these events, immune cells vary their phenotypes and functions over time, thus enabling the immune microenvironment to be “tumor-inhibiting” as well as “tumor-promoting” as a whole. Because of the association of tumoricidal T cell infiltration with favorable survival in cancer patients, the Immunoscore system was established. Critically, the tumoral Immunoscore serves as an indicator of CRC patient prognosis independent of patient TNM stage and suggests that patients with high Immunoscores in their tumors have prolonged survival in general. Accordingly, stratifications according to tumoral Immunoscores provide new insights into CRC in terms of comparing disease severity, forecasting disease progression, and making treatment decisions. An important application of this system will be to shed light on candidate selection in immunotherapy for CRC, because the T cells responsible for determining the Immunoscore serve as responders to immune checkpoint inhibitors. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration of cytotoxic and memory T cells, while information concerning the survival and function of these cells is still absent. Moreover, other infiltrates, such as dendritic cells, macrophages, and B cells, can still influence CRC prognosis, implying that those might also influence the therapeutic efficacy of immune checkpoint inhibitors. On these bases, this review is designed to introduce the Immunoscore system by presenting its clinical significance and application in CRC.
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Affiliation(s)
- Liang Guo
- Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Chuanlei Wang
- Department of Hepatobiliary Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiang Qiu
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoyu Pu
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
| | - Pengyu Chang
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China.,Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, China
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25
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Almangush A, Mäkitie AA, Triantafyllou A, de Bree R, Strojan P, Rinaldo A, Hernandez-Prera JC, Suárez C, Kowalski LP, Ferlito A, Leivo I. Staging and grading of oral squamous cell carcinoma: An update. Oral Oncol 2020; 107:104799. [PMID: 32446214 DOI: 10.1016/j.oraloncology.2020.104799] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/19/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is a common malignancy of the head and neck region. OSCC has a relatively low survival rate and the incidence of the disease is increasing in some geographic areas. Staging and grading of OSCC are established prerequisites for management, as they influence risk stratification and are the first step toward personalized treatment. The current AJCC/UICC TNM staging (8th edition, 2017) of OSCC has included significant modifications through the incorporation of depth of invasion in the T stage and extracapsular spread/extranodal extension in the N stage. Further modifications for AJCC 8 have been suggested. On the other hand, the World Health Organization (WHO) classification (4th edition, 2017) still endorses a simple, differentiation-based histopathologic grading system of OSCC (despite its low prognostic value) and ignores factors such as tumor growth pattern and dissociation, stromal reactions (desmoplasia, local immune response), and tumor-stroma ratio. The various controversies and possible developments of the current staging and grading criteria of OSCC are briefly discussed in this update together with possible applications of artificial intelligence in the context of screening and risk stratification.
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Affiliation(s)
- Alhadi Almangush
- Department of Pathology, University of Helsinki, Helsinki, Finland; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Institute of Biomedicine, Pathology, University of Turku, Turku, Finland; Faculty of Dentistry, University of Misurata, Misurata, Libya.
| | - Antti A Mäkitie
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Finland; Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden.
| | - Asterios Triantafyllou
- Department of Pathology, Liverpool Clinical Laboratories and School of Dentistry, University of Liverpool, Liverpool, UK.
| | - Remco de Bree
- Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
| | - Primož Strojan
- Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia.
| | | | | | - Carlos Suárez
- Instituto de Investigacion Sanitaria del Principado de Asturias and (CIBERONC), ISCIII, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, Oviedo, Spain
| | - Luiz P Kowalski
- Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center, Sao Paulo, Brazil; Head and Neck Surgery, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
| | - Alfio Ferlito
- Coordinator of the International Head and Neck Scientific Group, Padua, Italy.
| | - Ilmo Leivo
- Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.
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Watson MM, Lea D, Gudlaugsson E, Skaland I, Hagland HR, Søreide K. Prevalence of PD-L1 expression is associated with EMAST, density of peritumoral T-cells and recurrence-free survival in operable non-metastatic colorectal cancer. Cancer Immunol Immunother 2020; 69:1627-1637. [PMID: 32314040 PMCID: PMC7347699 DOI: 10.1007/s00262-020-02573-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/07/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Microsatellite instability (MSI) predict response to anti-PD1 immunotherapy in colorectal cancer (CRC). CRCs with MSI have higher infiltration of immune cells related to a better survival. Elevated Microsatellite Alterations at Tetranucleotides (EMAST) is a form of MSI but its association with PD-L1 expression and immune-cell infiltration is not known. METHODS A consecutive, observational cohort of patients undergoing surgery for CRC. EMAST and clinicopathological characteristics were investigated against PD-L1, as well as CD3 and CD8 expression in the invasive margin or tumour centre (Immunoscore). Difference in survival between groups was assessed by log rank test. RESULTS A total of 149 stage I-III CRCs patients, with a median follow up of 60.1 months. Patients with PD-L1+ tumours (7%) were older (median 79 vs 71 years, p = 0.045) and had EMAST+ cancers (OR 10.7, 95% CI 2.2-51.4, p = 0.001). Recurrence-free survival was longer in cancers with PD-L1+ immune cells (HR 0.35, 95% CI 0.16-0.76, p = 0.008, independent of EMAST) and high Immunoscore (HR 0.10, 95% CI 0.01-0.72, p = 0.022). Patients expressing PD-L1 in immune cells had longer disease-specific survival (HR 0.28, 95% CI 0.10-0.77, p = 0.014). CONCLUSIONS Higher Immunoscore (CD3/CD8 cells) and expression of tumour PD-L1 is found in CRCs with EMAST. Lymphocytic infiltrate and peritumoral PD-L1 expression have prognostic value in CRC.
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Affiliation(s)
- Martin M Watson
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Einar Gudlaugsson
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Ivar Skaland
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway
- Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Kjetil Søreide
- Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway.
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
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27
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Monaco SE, Dacic S, Seigh L, Hartman DJ, Xing J, Pantanowitz L. Quantitative image analysis for CD8 score in lung small biopsies and cytology cell-blocks. Cytopathology 2020; 31:393-401. [PMID: 32065467 DOI: 10.1111/cyt.12812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 02/08/2020] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Immunotherapy has shown promising results in non-small cell lung cancer (NSCLC), for which tumour-infiltrating cytotoxic (CD8+) T cells play a critical role. We investigated the utility of image analysis (IA) to quantify CD8+ T cells in a series of matched small biopsies and resections of NSCLC. METHODS CD8 immunohistochemistry was performed on cell-blocks (CB), core needle biopsies (CNB) and corresponding resections from primary NSCLCs. Slides were digitised using an Aperio AT2 scanner (Leica) and annotated by whole slide image (WSI) or fields of view occupied by tissue spots (TS). Quantitative IA was performed with a customised Aperio algorithm (Leica). CD8 scores (number of T cells with 1-3+ staining/total area) were then compared. RESULTS Forty-four cases with CB or CNB material and a corresponding resection were analysed. Average CD8 score was determined in CB (7.67 WSI, 77.67 TS) and/or CNB (47.35 WSI, 325.67 TS), and corresponding resections (190.35 WSI, 336.58 TS). CD8 score concordance was highest (78.6%) for CNBs using WSI annotation. Overall, small biopsies (CB or CNB) correlated with the resection in 71.4% cases using WSI and 63.3% cases using TS annotation. IA performed better for low CD8 scores. CONCLUSIONS These findings show that CD8 density in NSCLC can be quantified by IA in small biopsies and cell blocks, achieving the best concordance using WSI scores. Discrepancies were attributed to values near the cut-off and background detection of staining. These data warrant future studies with more cases and follow-up data to further investigate the clinical utility of IA for CD8 analysis in NSCLC.
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Affiliation(s)
- Sara E Monaco
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Sanja Dacic
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Lindsey Seigh
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Douglas J Hartman
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Juan Xing
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
| | - Liron Pantanowitz
- Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA
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28
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Wunder JS, Lee MJ, Nam J, Lau BY, Dickson BC, Pinnaduwage D, Bull SB, Ferguson PC, Seto A, Gokgoz N, Andrulis IL. Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation. Oncoimmunology 2020; 9:1737385. [PMID: 33457085 PMCID: PMC7790526 DOI: 10.1080/2162402x.2020.1737385] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins.
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Affiliation(s)
- Jay S Wunder
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Department of Surgery, University of Toronto, ON, Canada
| | - Minji J Lee
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Junghyun Nam
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Beatrice Y Lau
- Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, ON, Canada
| | - Brendan C Dickson
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, ON, Canada
| | | | - Shelley B Bull
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Peter C Ferguson
- University of Toronto Musculoskeletal Oncology Unit, Sinai Health System, Toronto, ON, Canada.,Department of Surgery, University of Toronto, ON, Canada
| | - Andrew Seto
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Nalan Gokgoz
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Irene L Andrulis
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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29
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Picard E, Verschoor CP, Ma GW, Pawelec G. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer. Front Immunol 2020; 11:369. [PMID: 32210966 PMCID: PMC7068608 DOI: 10.3389/fimmu.2020.00369] [Citation(s) in RCA: 334] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
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Affiliation(s)
- Emilie Picard
- Health Sciences North Research Institute, Sudbury, ON, Canada
| | | | - Grace W Ma
- Department of Surgery, Health Sciences North, Sudbury, ON, Canada
| | - Graham Pawelec
- Health Sciences North Research Institute, Sudbury, ON, Canada.,Department of Immunology, University of Tübingen, Tübingen, Germany
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30
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Wu X, Ke X, Ni Y, Kuang L, Zhang F, Lin Y, Lin W, Xiong X, Huang H, Lin X, Zhang H. Tumor-Infiltrating Immune Cells and PD-L1 as Prognostic Biomarkers in Primary Esophageal Small Cell Carcinoma. J Immunol Res 2020; 2020:8884683. [PMID: 33457428 PMCID: PMC7785377 DOI: 10.1155/2020/8884683] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 12/04/2020] [Accepted: 12/16/2020] [Indexed: 02/05/2023] Open
Abstract
Primary esophageal small cell carcinoma (PESCC) is a weakly prevalent but lethal malignancy with early metastasis and a poor prognosis. Currently, neither effective prognostic indicators nor curative therapies are available for PESCC. Immunotherapy has now evolved into one of the most promising therapies for cancer patients. Tumor-infiltrating immune cells which are integral to the tumor immune microenvironment (TIME) are recognized as highly important for prognosis prediction, while the responsiveness to immune checkpoint blockade may be subject to the features of TIME. In this study, we aim to identify the TIME and provide indication for the applicability of immune checkpoint therapy in PESCC. We found that PD-L1 expression was detected in 33.33% (27/81) of all the patients, mostly exhibiting a stroma-only pattern and that it was positively associated with tumor-infiltrating immune cells (CD4+, CD8+, and CD163+). In 74.07% of PD-L1-positive specimens, PD-L1+CD163+ cells were colocalized more with CD4+ than CD8+ T cells. 83.95% (68/81) of all the specimens were infiltrated with more CD4+ than CD8+ T cells. Further analysis showed FoxP3+ Tregs constituted 13-27% of the total CD4+ T cell population. The Kaplan--Meier analysis indicated several factors that contribute to poor survival, including negative PD-L1 expression, rich CD4 expression, rich FoxP3 expression, a low CD8/CD4 ratio, and a high FoxP3/CD8 ratio. A nomogram model was constructed and showed good performance for survival prediction. These results highlight that a suppressive TIME contributes to poor survival of patients with PESCC. TIME analyses might be a promising approach to evaluate the possibility and effect of immune checkpoint-based immunotherapeutics in PESCC patients.
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Affiliation(s)
- Xiao Wu
- Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiurong Ke
- Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
- Department of Surgery, Laboratory for Translational Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Yangpeng Ni
- Department of Pathology, Jieyang People's Hospital (Jieyang Affiliated Hospital, Sun Yat-Sen University), Jieyang, Guangdong, China
| | - Liping Kuang
- Department of Pathology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, Guangdong, China
| | - Fan Zhang
- Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yusheng Lin
- Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
- Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Wan Lin
- Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
| | - Xiao Xiong
- Department of General Surgery, The First Affiliated Hospital of Jinan University and Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, China
| | - Haihua Huang
- Department of Pathology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Xianjie Lin
- Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China
| | - Hao Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University and Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, China
- Research Center of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
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31
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Alexander PG, McMillan DC, Park JH. The local inflammatory response in colorectal cancer - Type, location or density? A systematic review and meta-analysis. Cancer Treat Rev 2019; 83:101949. [PMID: 31869737 DOI: 10.1016/j.ctrv.2019.101949] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. METHODS A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. RESULTS Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. CONCLUSION The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.
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Affiliation(s)
| | | | - James H Park
- School of Medicine, University of Glasgow, Glasgow, United Kingdom
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Chen F, Li Z, Deng C, Yan H. Integration analysis for novel lncRNA markers predicting tumor recurrence in human colon adenocarcinoma. J Transl Med 2019; 17:299. [PMID: 31470869 PMCID: PMC6717325 DOI: 10.1186/s12967-019-2049-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 08/25/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Numerous evidence has suggested that long non-coding RNA (lncRNA) acts an important role in tumor biology. This study focuses on the identification of novel prognostic lncRNA biomarkers predicting tumor recurrence in human colon adenocarcinoma. METHODS We obtained the research data from The Cancer Genome Atlas (TCGA) database. The interaction among different expressed lncRNA, miRNA and mRNA markers between colon adenocarcinoma patients with and without tumor recurrence were verified with miRcode, starBase and miRTarBase databases. We established the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network based on the verified association between the selected markers. We performed the functional enrichment analysis to obtain better understanding of the selected lncRNAs. Then we use multivariate logistic regression to identify the prognostic lncRNA markers with covariates. We also generated a nomogram predicting tumor recurrence risk based on the identified lncRNA biomarkers and clinical covariates. RESULTS We included 12,727 lncRNA, 1881 miRNA and 47,761 mRNA profiling and clinical features for 113 colon adenocarcinoma patients obtained from the TCGA database. After filtration, we used 37 specific lncRNAs, 60 miRNAs and 148 mRNAs in the ceRNA network analysis. We identified five lncRNAs as prognostic lncRNA markers predicting tumor recurrence in colon adenocarcinoma, in which four of them were identified for the first time. Finally, we generated a nomogram illustrating the association between the identified lncRNAs and the tumor recurrence risk in colon adenocarcinoma. CONCLUSIONS The four newly identified lncRNA biomarkers might be potential prognostic biomarkers predicting tumor recurrence in colon adenocarcinoma. We recommend that further clinical and fundamental researches be conducted on the identified lncRNA markers.
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Affiliation(s)
- Fangyao Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Xi’an Jiaotong University Health Science Center, 76 Yanta Xilu Road, Xi’an, 710061 Shaanxi China
| | - Zhe Li
- First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Xilu Road, Xi’an, 710061 Shaanxi China
| | - Changyu Deng
- Department of Preventive Medicine, Shantou University Medical College, 22 Xinling Road, Jinping District, Shantou, 515041 Guangdong China
| | - Hong Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Xi’an Jiaotong University Health Science Center, 76 Yanta Xilu Road, Xi’an, 710061 Shaanxi China
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Yomoda T. ASO Author Reflections: Analysis of PD-L1 Expression and Immunoscore in Colorectal Cancer. Ann Surg Oncol 2019; 26:658-659. [PMID: 31332636 DOI: 10.1245/s10434-019-07363-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Indexed: 11/18/2022]
Affiliation(s)
- Takato Yomoda
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
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Kim S, Nam SJ, Park C, Kwon D, Yim J, Song SG, Ock CY, Kim YA, Park SH, Kim TM, Jeon YK. High tumoral PD-L1 expression and low PD-1 + or CD8 + tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system. Oncoimmunology 2019; 8:e1626653. [PMID: 31428525 DOI: 10.1080/2162402x.2019.1626653] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/27/2019] [Accepted: 05/29/2019] [Indexed: 01/07/2023] Open
Abstract
We investigated the clinicopathological role of the PD-1/PD-L1 pathway in primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) arising in the immune-privileged site. PD-L1 immunostaining of ≥30% of tumor cells was defined as tPD-L1+, and PD-L1 immunostaining of ≥30% of total cellularity, including tumor and non-tumoral cells, as tmPD-L1+ . PD-1+ and CD8+ tumor-infiltrating lymphocytes (TILs) were enumerated. Thirty-five cases (35.7%) were tPD-L1+ and 47 cases (48%) were tmPD-L1+ . The number of TILs was greater in tmPD-L1+ cases than in tmPD-L1- cases (CD8+, P= .050; PD-1+, P= .019). tPD-L1+ and tmPD-L1+ cases tended to have a poor performance status. In contrast, the numbers of CD8+ and PD-1+ TILs tended to be higher in patients with a good performance status and MYC/BCL2 negativity. Patients with tPD-L1+ had a worse overall survival (P= .026), and those with increased CD8+ or PD-1+ TILs tended to have a better overall survival (P= .081 and 0.044, respectively). Tumoral PD-L1 expression and the number of PD-1+ TILs were independent prognostic factors. tPD-L1+ patients with a small number of CD8+ or PD-1+ TILs had the worst prognosis, and tPD-L1- patients with a large number of CD8+ or PD-1+ TILs had the best prognosis. In validation group, increased CD8+ or PD-1+ TILs were significantly associated with a prolonged survival, but PD-L1 had no prognostic significance. In conclusion, PD-L1 is frequently expressed in tumor cells and the immune microenvironment of PCNS-DLBCL and is correlated with increased TILs. PD-L1 and CD8+ and PD-1+ TILs have potential as prognostic biomarkers and therapeutic targets in PCNS-DLBCL.
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Affiliation(s)
- Sehui Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, Seoul, Republic of Korea
| | - Changhee Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dohee Kwon
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Jeemin Yim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Geun Song
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chan-Young Ock
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young A Kim
- Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul Republic of Korea
| | - Sung Hye Park
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae Min Kim
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
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