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Papachristos A, Zhou L, Sheen A, Sywak M, Robinson B, Clifton-Bligh R, Sidhu S, Gill AJ. Tumor-Infiltrating Lymphocytes Assessed Using the International TILs Working Group System Are Not Prognostic in Medullary Thyroid Cancer. Thyroid 2025. [PMID: 39868721 DOI: 10.1089/thy.2024.0595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Background: Tumor-infiltrating lymphocytes (TILs) are a protective prognostic factor in several solid tumors and predict response to immune checkpoint inhibitor therapy. The prognostic impact of TILs in medullary thyroid cancer (MTC) is poorly understood. Materials and Methods: In this retrospective cohort study, we assessed the TILs profile of primary MTC tumors using the International TILs Working Group system and correlated this with clinicopathological prognostic variables, including the International Medullary Thyroid Cancer Grading System (IMTCGS) grade and survival outcomes. Results: We identified 71 patients with primary MTC tumors who were treated surgically between 1995 and 2016 at the Royal North Shore Hospital in Sydney, Australia. The median (interquartile range) duration of follow-up was 69 (90) months. Using the ITWG system, all patients with MTC had low TILs, with a median (range) of 3% (0-10%). This group was further subdivided into "very low" (0-4%) and "low" (5-10%), and on Cox regression analysis, increasing TILs were associated with increased local recurrence (log-rank p = 0.022, odds ratio [OR] 1.94 [confidence interval or CI 0.61-6.16], p = 0.26), reduced disease-specific survival (log-rank p = 0.015, OR 5.11 [CI 1.01-26.0], p = 0.049), and a trend to decreased distant metastasis-free survival (log-rank p = 0.14). When examining the association between TILs and other prognostic factors, only "high IMTCGS grade" was significantly associated with increased TILs (OR 7.29 [CI 1.21-43.90], p = 0.015). In the multivariable logistic regression analysis, there was no significant association between TILs and local recurrence or disease-specific survival. Conclusions: In our study, the prognostic value of TILs in MTC was limited. Even high-grade MTC can be considered an immune quiescent tumor, and the adverse prognostic factors associated with higher grade tumors outweigh the marginal increase in immune recognition associated with a slight increase in TILs. The low level of TILs in MTC and their lack of correlation with survival suggest that immune checkpoint inhibitor therapy may not be effective.
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Affiliation(s)
- Alexander Papachristos
- Department of Endocrine Surgery, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Lydia Zhou
- Department of Endocrine Surgery, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
| | - Amy Sheen
- Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
| | - Mark Sywak
- Department of Endocrine Surgery, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Bruce Robinson
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
- Department of Endocrinology and Diabetes, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia
| | - Roderick Clifton-Bligh
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
- Department of Endocrinology and Diabetes, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia
| | - Stan Sidhu
- Department of Endocrine Surgery, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Anthony J Gill
- Faculty of Medicine and Health, Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
- Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, Australia
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Characterization of the tumor-infiltrating lymphocyte landscape in sinonasal mucosal melanoma. Pathol Res Pract 2023; 241:154289. [PMID: 36584498 DOI: 10.1016/j.prp.2022.154289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are important prognostic biomarkers in several types of cancers. The interplay between TIL subgroups and immune checkpoint molecules like programmed cell death ligand 1 (PD-L1) is a promising target for immunotherapy. However, the TIL landscape in sinonasal mucosal melanoma (SNMM) has not been sufficiently characterized yet and the prognostic value of TIL subgroups and PD-L1 expression remains uncertain. Here, we investigated subsets of TILs (CD3+, CD4+, CD8+, CD20+) and PD-L1 expression patterns in SNMM and assessed their prognostic value for recurrence-free and overall survival. METHODS Immunohistochemical staining for CD3, CD4, CD8, CD20 and PD-L1 was performed on tumor tissue from 27 patients with primary SNMM. Patient history was obtained and associations between TIL subgroups or PD-L1 expression and AJCC tumor stage, overall survival, and recurrence-free survival were retrospectively analyzed. RESULTS Patients with high CD3+ and CD8+ TILs in the primary tumor survived significantly longer than patients with SNMMs with a low number of CD3+ and CD8+ TILs. High CD3+ and high CD8+ TILs were associated with the lower T3 stage and increased 5-year survival. PD-L1 positivity in tumor cells was associated with advanced tumor stage. CONCLUSION Our results indicate that high densities of CD3+ and CD8+ TILs are strong positive prognostic biomarkers for survival in SNMM. Prospective studies with larger case numbers are warranted to confirm our findings.
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Eismann L, Rodler S, Buchner A, Schulz GB, Volz Y, Bischoff R, Ebner B, Westhofen T, Casuscelli J, Waidelich R, Stief C, Schlenker B, Ledderose S. Identification of the Tumor Infiltrating Lymphocytes (TILs) Landscape in Pure Squamous Cell Carcinoma of the Bladder. Cancers (Basel) 2022; 14:cancers14163999. [PMID: 36010989 PMCID: PMC9406640 DOI: 10.3390/cancers14163999] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/07/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Background: Tumor infiltrating lymphocytes (TILs) are known as important prognostic biomarkers and build the fundament for immunotherapy. However, the presence of TILs and its impact on outcome in pure squamous cell carcinoma (SCC) of the bladder remains uncertain. Methods: Out of 1600 patients undergoing radical cystectomy, 61 patients revealed pure bladder SCC in the final histopathological specimen. Retrospectively, immunohistochemical staining was performed on a subset of TILs (CD3+, CD4+, CD8+, CD20+). Endpoints were overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). The Kaplan−Meier method was used to evaluate survival outcomes. Results: Strong infiltration of CD3+ was found in 27 (44%); of CD4+ in 28 (46%); of CD8+ in 26 (43%); and of CD20+ in 27 tumors (44%). Improved OS was observed for strong CD3+ (p < 0.001); CD4+ (p = 0.045); CD8+ (p = 0.001); and CD20+ infiltration (p < 0.001). Increased rates of PFS were observed for CD3+ (p = 0.025) and CD20+ TILs (p = 0.002). In multivariate analyses, strong CD3+ (HR: 0.163, CI: 0.044−0.614) and strong CD8+ TILs (HR: 0.265, CI: 0.081−0.864) were revealed as predictors for OS and the strong infiltration of CD20+ cells (HR: 0.095, CI: 0.019−0.464) for PFS. Conclusions: These first results of TILs in bladder SCC revealed predictive values of CD3+, CD8+ and CD20+.
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Affiliation(s)
- Lennert Eismann
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
- Correspondence:
| | - Severin Rodler
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Alexander Buchner
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Gerald Bastian Schulz
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Yannic Volz
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Robert Bischoff
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Benedikt Ebner
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Thilo Westhofen
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Jozefina Casuscelli
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Raphaela Waidelich
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Christian Stief
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Boris Schlenker
- Department of Urology, University Hospital Munich, Ludwig-Maximilian-University, 81377 Munich, Germany
| | - Stephan Ledderose
- Department of Pathology, University Hospital Munich, Ludwig-Maximilian-University, 80337 Munich, Germany
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Ledderose S, Rodler S, Eismann L, Ledderose G, Ledderose C. Tumor-infiltrating lymphocytes predict survival in ≥ pT2 urothelial bladder cancer. Pathol Res Pract 2022; 237:154037. [PMID: 35908386 DOI: 10.1016/j.prp.2022.154037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/20/2022] [Indexed: 10/17/2022]
Abstract
Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in several types of cancers, including genitourinary cancers. However, multiple different scoring methods used to assess TILs complicate the comparison of different studies and are not always suitable for daily practice. In 2014, the International TILs Working Group (ITWG) proposed a simple and robust assessment method for a more standardized evaluation of TILs. Here, we validated this system in muscle-invasive urinary bladder cancer (MIBC). Patient history and histologic specimens from 203 patients with MIBC were retrospectively analyzed. The stromal TIL (sTIL) score was determined using the ITWG system and 3 groups were defined according to the degree of stromal lymphocytic infiltration: low (0-10%), intermediate (10-55%) and high (55-100%). Associations between sTIL score, clinicopathological variables, tumor-specific survival (TSS), overall survival (OS), and disease-free survival (DFS) were analyzed. High stromal lymphocytic infiltration was associated with significantly higher OS, TSS and DFS when compared to low grade sTILs. The survival benefit remained statistically significant in multivariate analyses, confirming that sTILs are a strong independent positive prognostic factor in patients with MIBC. In summary, the degree of sTILs as defined by the ITWG robustly predicts survival in MIBC patients. Prospective studies with larger case numbers are needed to determine whether sTILs should be included in staging guidelines and how they could aid in therapeutic decision making.
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Affiliation(s)
- Stephan Ledderose
- Department of Pathology, Ludwig Maximilian University Munich, Germany.
| | - Severin Rodler
- Department of Urology, Ludwig Maximilian University Munich, Germany
| | - Lennert Eismann
- Department of Urology, Ludwig Maximilian University Munich, Germany
| | - Georg Ledderose
- Department of Oto-Rhino-Laryngology, Ludwig Maximilian University Munich, Germany
| | - Carola Ledderose
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Odate T, Le MK, Kawai M, Kubota M, Yamaguchi Y, Kondo T. Tumor-infiltrating lymphocytes in breast FNA biopsy cytology: a predictor of tumor-infiltrating lymphocytes in histologic evaluation. Cancer Cytopathol 2022; 130:336-343. [PMID: 35129867 DOI: 10.1002/cncy.22551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are associated with various clinicopathological features. Using cytologic specimens for assessing TILs remains to be established. This retrospective study aimed to establish a practical method to assess TILs in cytologic samples. METHODS The authors found 1101 breast fine-needle aspiration biopsy (FNAB) cytology samples in their hospital, and 214 of them met the inclusion criteria. The TILs score was evaluated using histologic slides, and breast cancers were divided into 2 groups: low- (<60%) and high-TILs (≥60%). Training and validation tests composed of 50 breast cancer samples each were constructed. A cytologic TILs (cTILs) score was introduced to evaluate lymphocytes in FNAB cytology and it was compared with histologically evaluated TILs. The cTILs score was calculated by subtracting the number of neutrophils from the number of lymphocytes surrounding the tumor cells. RESULTS In the training test, a 2-tier system with low- and high-TILs groups showed a large area under the curve (AUC) (0.943; 95% confidence interval [CI], 0.84-0.99). A cTILs score cutoff value of >8 had 87.5% sensitivity and 90.5% specificity. In the validation test, the AUC was 0.79 (95% CI, 0.6-0.93) whereas sensitivity and specificity were 57% and 89.5%, respectively. When small tumors <0.5 cm were excluded, the AUC improved to 0.93 (95% CI, 0.83-1.0), and sensitivity and specificity were 80% and 88.5%, respectively. CONCLUSIONS The cTILs scoring system had acceptable reproducibility and concordance with TILs on histologic samples for tumors ≥0.5 cm. Cytologic evaluation can potentially substitute for histologic evaluation of TILs.
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Affiliation(s)
- Toru Odate
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Minh-Khang Le
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Masataka Kawai
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Mizuki Kubota
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Yohei Yamaguchi
- Department of Pathology, University of Yamanashi, Chuo, Japan
| | - Tetsuo Kondo
- Department of Pathology, University of Yamanashi, Chuo, Japan
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Whiteside TL. Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:89-106. [PMID: 35165861 PMCID: PMC9113058 DOI: 10.1007/978-3-030-91311-3_3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor-infiltrating lymphocytes (TIL) are an important component of the tumor environment. Their role in tumor growth and progression has been debated for decades. Today, emphasis has shifted to beneficial effects of TIL for the host and to therapies optimizing the benefits by reducing immune suppression in the tumor microenvironment. Evidence indicates that when TILs are present in the tumor as dense aggregates of activated immune cells, tumor prognosis and responses to therapy are favorable. Gene signatures and protein profiling of TIL at the population and single-cell levels provide clues not only about their phenotype and numbers but also about TIL potential functions in the tumor. Correlations of the TIL data with clinicopathological tumor characteristics, clinical outcome, and patients' survival indicate that TILs exert influence on the disease progression, especially in colorectal carcinomas and breast cancer. At the same time, the recognition that TIL signatures vary with time and cancer progression has initiated investigations of TIL as potential prognostic biomarkers. Multiple mechanisms are utilized by tumors to subvert the host immune system. The balance between pro- and antitumor responses of TIL largely depends on the tumor microenvironment, which is unique in each cancer patient. This balance is orchestrated by the tumor and thus is shifted toward the promotion of tumor growth. Changes occurring in TIL during tumor progression appear to serve as a measure of tumor aggressiveness and potentially provide a key to selecting therapeutic strategies and inform about prognosis.
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Affiliation(s)
- Theresa L Whiteside
- Departments of Pathology and Immunology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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Sharma S, George P, Waddell N. Precision diagnostics: Integration of tissue pathology and genomics in cancer. Pathology 2021; 53:809-817. [PMID: 34635323 DOI: 10.1016/j.pathol.2021.08.003] [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: 04/14/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/09/2022]
Abstract
Traditionally, cancer diagnosis and management has been reactionary in that symptoms lead to investigations, then a diagnosis is followed by clinical management. This process is heavily dependent on tissue diagnosis mainly by histopathology and to a lesser extent, cytopathology. However, in recent times there has been a shift towards precision medicine to enable prevention, prediction and personalisation in healthcare. The core of precision medicine is optimising therapeutic benefit for patients, by using genomic and molecular profiling, analogously termed precision pathology. This review explores (1) the evolution of pathology from a para-clinical discipline to a mainstream medical field integral to oncology tumour boards; (2) its critical role in preventative, diagnostic, therapeutic and follow-up cancer care; (3) the future of tissue pathology in the era of precision oncology; and (4) how pathologists may evolve to future-proof their profession.
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Affiliation(s)
- Sowmya Sharma
- Medlab Pathology, Auburn, NSW, Australia; QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia.
| | - Peter George
- Medlab Pathology, Auburn, NSW, Australia; genomiQa, Brisbane, Qld, Australia
| | - Nicola Waddell
- QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia; genomiQa, Brisbane, Qld, Australia
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Mashukov A, Shapochka D, Seleznov O, Kobyliak N, Falalyeyeva T, Kirkilevsky S, Yarema R, Sulaieva O. Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma: Relation to the immune cycle. World J Gastroenterol 2021; 27:5259-5271. [PMID: 34497449 PMCID: PMC8384749 DOI: 10.3748/wjg.v27.i31.5259] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/01/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Various histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete. AIM To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept. METHODS In total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated. RESULTS We found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters. CONCLUSION These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.
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Affiliation(s)
- Artem Mashukov
- Department of Oncology, Odessa National Medical University, Odessa 65082, Ukraine
| | - Dmytro Shapochka
- Department of Molecular Pathology and Genetics, Medical Laboratory CSD, Kyiv 03022, Ukraine
| | - Oleksii Seleznov
- Department of Pathology, Medical Laboratory CSD, Kyiv 03022, Ukraine
| | - Nazarii Kobyliak
- Department of Pathology, Medical Laboratory CSD, Kyiv 03022, Ukraine
- Department of Endocrinology, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Tetyana Falalyeyeva
- Biomedicine, Educational-Scientific Center, "Institute of Biology and Medicine" Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | | | - Roman Yarema
- Department of Oncology and Medical Radiology, Danylo Halytsky Lviv National Medical University, Lviv 79010, Ukraine
| | - Oksana Sulaieva
- Department of Pathology, Medical Laboratory CSD, Kyiv 03022, Ukraine
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Bezerra TMM, Monteiro BVDB, Pereira JDS, Silva LAB, Nonaka CFW, Silveira ÉJDD, Miguel MCDC. Assessment of the presence of interleukin 17 + macrophages and Th17 cells in situ in lip and oral tongue cancer. Hum Immunol 2021; 82:945-949. [PMID: 34426031 DOI: 10.1016/j.humimm.2021.08.006] [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: 03/27/2021] [Revised: 07/19/2021] [Accepted: 08/10/2021] [Indexed: 11/19/2022]
Abstract
Increasing clinical evidence indicates that Th17 cells may promote or inhibit tumor progression, however the exact role of these cells in Oral Squamous Cell Carcinoma (OSCCs) pathogenesis and progression remains unclear. Tumor associated macrophages are highly plastic phenotype cells which can differentiate as M1 or M2. The mechanism and cellular phenotype of IL-17 expressing macrophages are unknown. 40 cases of lip and 28 of tongue SCCs were submitted to immunohistochemical analysis, and histologically graded. In tongue cases TNM was analyzed. The number of IL-17+ T cells was higher in lip SCC (p = 0.028). IL-17+ macrophages was greater in tongue SCC (p = 0.014). There were more IL-17+ macrophages in the high-grade malignancy oral tongue SCCs (p = 0.016), yet there was no significant difference in the numbers of RORγt+ lymphocytes by histopathological or TNM analysis. This study provides evidence concerning IL-17's pleiotropic roles, being possibly dependent on its cellular sources in the tumor microenvironment.
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Affiliation(s)
| | | | - Joabe Dos Santos Pereira
- Department of Pathology, Universidade Federal do Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
| | - Luiz Arthur Barbosa Silva
- School of Dentistry, Dentistry Department, Universidade Federal do Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil
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Almangush A, Leivo I, Mäkitie AA. Biomarkers for Immunotherapy of Oral Squamous Cell Carcinoma: Current Status and Challenges. Front Oncol 2021; 11:616629. [PMID: 33763354 PMCID: PMC7982571 DOI: 10.3389/fonc.2021.616629] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/29/2021] [Indexed: 12/11/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) forms a major health problem in many countries. For several decades the management of OSCC consisted of surgery with or without radiotherapy or chemoradiotherapy. Aiming to increase survival rate, recent research has underlined the significance of harnessing the immune response in treatment of many cancers. The promising finding of checkpoint inhibitors as a weapon for targeting metastatic melanoma was a key event in the development of immunotherapy. Furthermore, clinical trials have recently proven inhibitor of PD-1 for treatment of recurrent/metastatic head and neck cancer. However, some challenges (including patient selection) are presented in the era of immunotherapy. In this mini-review we discuss the emergence of immunotherapy for OSCC and the recently introduced biomarkers of this therapeutic strategy. Immune biomarkers and their prognostic perspectives for selecting patients who may benefit from immunotherapy are addressed. In addition, possible use of such biomarkers to assess the response to this new treatment modality of OSCC will also be discussed.
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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.,Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.,Faculty of Dentistry, University of Misurata, Misurata, Libya
| | - Ilmo Leivo
- Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.,Department of Pathology, Turku University Central Hospital, Turku, Finland
| | - 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, Helsinki, Finland.,Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
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11
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Lang-Schwarz C, Melcher B, Dregelies T, Norouzzadeh Z, Rund-Küffner S, Lang-Schwarz K, Vieth M, Sterlacci W. Adjuvant chemotherapy in stage II and III colon cancer: the role of the "budding and TILs-(tumor-infiltrating lymphocytes) combination" as tumor-host antagonists. Int J Colorectal Dis 2021; 36:1765-1779. [PMID: 33745027 PMCID: PMC8279987 DOI: 10.1007/s00384-021-03896-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE To analyze the influence of adjuvant chemotherapy on the combination of tumor budding and tumor-infiltrating lymphocytes (TILs) in stage II and III colon cancer and to elucidate its potential value for adjuvant treatment decisions. METHODS 306 patients with stage II and 205 patients with stage III colon cancer diagnosed between 2005 and 2016 who had undergone surgery in a curative setting were enrolled. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and the criteria of the International TILs Working Group (ITWG). Combinations of budding and TILs were analyzed, and the influence of adjuvant chemotherapy was assessed. RESULTS In stage II colon cancer, stratification into the four budding/TILs groups showed no significant differences in overall survival (OS) between the chemotherapy and the surgery-alone group, not even in cases with high-risk features. In stage III colon cancer, patients with low budding/high TILs benefited significantly from chemotherapy (p=0.005). Patients with high budding/low TILs as well as high budding/high TILs showed a trend to benefit from adjuvant treatment. However, no chemotherapy benefit was seen for the low budding/low TIL group. CONCLUSIONS The budding/TIL combination identified subgroups in stage II and III colon cancer with and without benefit from adjuvant treatment. The results this study suggest that the combination of budding and TILs as tumor-host antagonists might be an additional helpful tool in adjuvant treatment decisions in stage II and III colon cancer.
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Affiliation(s)
- Corinna Lang-Schwarz
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Balint Melcher
- Institute of Pathology, Koblenz, Franz-Weis-Str. 13, 56073 Koblenz, Germany
| | - Theresa Dregelies
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Zahra Norouzzadeh
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Stefanie Rund-Küffner
- Department of Internal Medicine, Sana Klinik Pegnitz, GmbH, Langer Berg 12, 91257 Pegnitz, Germany
| | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - William Sterlacci
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
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12
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Assessment of Tumor-infiltrating Lymphocytes Using International TILs Working Group (ITWG) System Is a Strong Predictor of Overall Survival in Colorectal Carcinoma: A Study of 1034 Patients. Am J Surg Pathol 2020; 44:536-544. [PMID: 31743129 DOI: 10.1097/pas.0000000000001409] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The presence of increased tumor-infiltrating lymphocytes (TILs) is established as a positive prognostic factor in many malignancies including colorectal carcinoma (CRC). However, multiple different approaches have been used to assess TILs. In 2014, the International TILs Working Group (ITWG) proposed a standardized methodology for evaluating TILs, initially in the context of breast cancer, but subsequently expanded to other malignancies. To date, the efficacy of the ITWG system has not been investigated in a large cohort of all-stage CRC. We, therefore, sought to validate this system in CRC. We used the ITWG system to assess the density of stromal TILs in an unselected cohort of 1034 CRC patients undergoing primary tumor resection at our institution. The percentage TILs' score was categorized into 3 groups: low (0% to 10%), intermediate (15% to 50%), and high (55% to 100%). The mean survival was 53, 67, and 75 months, respectively (P=0.0001). This survival benefit remained statistically significant in multivariate analyses (P=0.0001) and subgroup analyses of mismatch repair-proficient CRCs (P=0.0001), mismatch repair-deficient CRCs (P=0.031), BRAFV600E-mutant CRCs (P=0.0001), and BRAF wild-type CRCs (P=0.001). The predictive value of TILs assessed using the ITWG system was superior to the assessment of intraepithelial lymphocyte performed prospectively using a standard system requiring ≥5 lymphocytes per high-powered field in direct contact with tumor cells or between tumor clusters. We conclude that the ITWG system for assessing TILs is a powerful predictor of all-cause survival in CRC independent of many prognostic factors and superior to the assessment of intraepithelial lymphocytes using a traditional system.
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13
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Sales de Sá R, Miranda Galvis M, Mariz BALA, Leite AA, Schultz L, Almeida OP, Santos-Silva AR, Pinto CAL, Vargas PA, Gollob KJ, Kowalski LP. Increased Tumor Immune Microenvironment CD3+ and CD20+ Lymphocytes Predict a Better Prognosis in Oral Tongue Squamous Cell Carcinoma. Front Cell Dev Biol 2020; 8:622161. [PMID: 33718347 PMCID: PMC7951138 DOI: 10.3389/fcell.2020.622161] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/18/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Oral tongue squamous cell carcinoma (OTSCC) causes over 350,000 cases annually and particularly impacts populations in developing countries. Smoking and alcohol consumption are major risk factors. Determining the role of the tumor immune microenvironment (TIME) in OTSCC outcomes can elucidate immune mechanisms behind disease progression, and can potentially identify prognostic biomarkers. Methods: We performed a retrospective study of 48 OTSCC surgical specimens from patients with tobacco and alcohol exposures. A panel of immunoregulatory cell subpopulations including T (CD3, CD4, CD8) and B (CD20) lymphocytes, dendritic cells (CD1a, CD83), macrophages (CD68), and immune checkpoint molecules programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) were analyzed using immunohistochemistry. The levels of immune effector cell subpopulations and markers were analyzed in relation to overall survival. Results: Pathological characteristics of the tumor microenvironment included inflammatory infiltrates (83.3%), desmoplasia (41.6%), and perineural invasion (50.0%). The TIME contained high levels of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+), as well as immature (CD1a) and mature (CD83) dendritic cells, PD-1, and PD-L1. Higher numbers of TIME infiltrating CD3+ T cells and CD20+ B cells were predictive of better survival, while higher levels of CD83+ mature dendritic cells predicted better survival. CD3+ T cells were identified as an independent prognostic marker for OTSCC. Lastly, CD3+ T cells were strongly correlated with the number of CD8+ cells and PD-L1 expression. Conclusion: Our findings provide evidence that the TIME profile of OTSSC impacted prognosis. The high expression of CD3+ T cells and B cells are predictive of better overall survival and indicative of an immunologically active, inflammatory TIME in patients with better survival. The number of CD3+ T cells was an independent prognostic marker.
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Affiliation(s)
- Raísa Sales de Sá
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Marisol Miranda Galvis
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
| | | | - Amanda Almeida Leite
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Luciana Schultz
- Department of Anatomic Pathology, Instituto de Anatomia Patologica–IAP, Santa Barbara d'Oeste, Brazil
| | - Oslei Paes Almeida
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Alan Roger Santos-Silva
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | | | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Kenneth John Gollob
- International Research Center, A. C. Camargo Cancer Center, São Paulo, Brazil
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Center, São Paulo, Brazil
- Head and Neck Surgery Department, Medical School, University of São Paulo, São Paulo, Brazil
- *Correspondence: Luiz Paulo Kowalski
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14
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Castaneda CA, Castillo M, Aliaga K, Bernabe LA, Casavilca S, Sanchez J, Torres-Cabala CA, Gomez HL, Mas L, Dunstan J, Cotrina JM, Abugattas J, Chavez I, Ruiz E, Montenegro P, Rojas V, Orrego E, Galvez-Nino M, Felix B, Landa-Baella MP, Vidaurre T, Villa MR, Zevallos R, Taxa L, Guerra H. Level of tumor-infiltrating lymphocytes and density of infiltrating immune cells in different malignancies. Biomark Med 2019; 13:1481-1491. [DOI: 10.2217/bmm-2019-0178] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Aim: To correlate levels of tumor-infiltrating lymphocytes (TIL) evaluated using the International Immuno-Oncology Biomarker Working Group methodology, and both density of tumor-infiltrating immune cell and clinicopathological features in different malignancies. Methods: 209 pathological samples from gastric cancer, cervical cancer (CC), non-small-lung cancer, cutaneous melanoma (CM) and glioblastoma were tested for TIL in hematoxylin eosin, and density of CD3+, CD4+, CD8+, CD20+, CD68+ and CD163+ cells by digital analysis. Results: TIL levels were higher in invasive margin compartments (IMC). TIL in IMC, intratumoral and stromal compartments predicted survival. CC and gastric cancer had higher TIL in intratumoral; CC and CM had higher TIL in stromal compartment and IMC. CM had the highest density of lymphocyte and macrophage populations. CD20 density was associated with survival in the whole series. Conclusion: Standardized evaluation of TIL levels may provide valuable prognostic information in a spectrum of different malignancies.
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Affiliation(s)
- Carlos A Castaneda
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
- Faculty of Health Sciences, Universidad Científica del Sur, Lima 15067, Peru
| | - Miluska Castillo
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Karina Aliaga
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis A Bernabe
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Sandro Casavilca
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Joselyn Sanchez
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Carlos A Torres-Cabala
- Departments of Pathology & Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Henry L Gomez
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis Mas
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jorge Dunstan
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Jose M Cotrina
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Julio Abugattas
- Department of Soft Tissue Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Ivan Chavez
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Eloy Ruiz
- Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Paola Montenegro
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Victor Rojas
- Department of Chest Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Enrique Orrego
- Department of Neurosurgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Marco Galvez-Nino
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Brayam Felix
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Maria P Landa-Baella
- Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Tatiana Vidaurre
- Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Maria R Villa
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Rocio Zevallos
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Luis Taxa
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
| | - Henry Guerra
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
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15
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Hofman P, Badoual C, Henderson F, Berland L, Hamila M, Long-Mira E, Lassalle S, Roussel H, Hofman V, Tartour E, Ilié M. Multiplexed Immunohistochemistry for Molecular and Immune Profiling in Lung Cancer-Just About Ready for Prime-Time? Cancers (Basel) 2019; 11:cancers11030283. [PMID: 30818873 PMCID: PMC6468415 DOI: 10.3390/cancers11030283] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/23/2019] [Accepted: 02/25/2019] [Indexed: 12/31/2022] Open
Abstract
As targeted molecular therapies and immuno-oncology have become pivotal in the management of patients with lung cancer, the essential requirement for high throughput analyses and clinical validation of biomarkers has become even more intense, with response rates maintained in the 20%–30% range. Moreover, the list of treatment alternatives, including combination therapies, is rapidly evolving. The molecular profiling and specific tumor-associated immune contexture may be predictive of response or resistance to these therapeutic strategies. Multiplexed immunohistochemistry is an effective and proficient approach to simultaneously identify specific proteins or molecular abnormalities, to determine the spatial distribution and activation state of immune cells, as well as the presence of immunoactive molecular expression. This method is highly advantageous for investigating immune evasion mechanisms and discovering potential biomarkers to assess mechanisms of action and to predict response to a given treatment. This review provides views on the current technological status and evidence for clinical applications of multiplexing and how it could be applied to optimize clinical management of patients with lung cancer.
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Affiliation(s)
- Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
- Team 4, Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM U1081/UMR CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice 06107, France.
| | - Cécile Badoual
- Department of Pathology, Hôpital Européen Georges Pompidou, APHP, Paris 75015, France.
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, Paris 75015, France.
| | - Fiona Henderson
- Department EMEA, Indica Labs, 2469 Corrales Rd Bldg. A-3 Corrales, NM 87048, USA.
| | - Léa Berland
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
| | - Marame Hamila
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
| | - Elodie Long-Mira
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
- Team 4, Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM U1081/UMR CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice 06107, France.
| | - Sandra Lassalle
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
- Team 4, Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM U1081/UMR CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice 06107, France.
| | - Hélène Roussel
- Department of Pathology, Hôpital Européen Georges Pompidou, APHP, Paris 75015, France.
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, Paris 75015, France.
| | - Véronique Hofman
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
- Team 4, Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM U1081/UMR CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice 06107, France.
| | - Eric Tartour
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, Paris 75015, France.
- Department of Immunology, Hôpital Européen Georges Pompidou, Paris 75015, France.
| | - Marius Ilié
- Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d'Azur, Nice 06000, France.
- Team 4, Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM U1081/UMR CNRS 7284, FHU OncoAge, Université Côte d'Azur, Nice 06107, France.
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