Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC)

Mesnage, Soizick; Auguste, Aurélie; Genestie, Catherine; Dunant, Ariane; Pain, Erwann; Drusch, Françoise; Gouy, Sébastien; Morice, Philippe; Bentivegna, Enrica; Lhommé, C.; Pautier, Patricia; Michels, Judith; Formal, Audrey Le; Cheaib, Bianca; Adam, Julien; Leary, Alexandra

doi:10.1093/annonc/mdw625

Cited by 139 publications

(113 citation statements)

References 22 publications

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“…HGSOCs are characterized by genomic alterations and instability, and DNA copy number abnormalities. In 2011, an analysis of 489 HGSOC samples found that TP53 mutations were presented in 96% of tumours, and homologous repair(HR) gene alterations were shown in about 50% of tumours, including germline mutations in either BRCA1 (9%) or BRCA2 (8%) and also somatic mutations in either one of these 2 genes (3%) . To this end, we classified the samples by TP53, BRCA1, BRCA2 abnormalities.…”

Section: Resultsmentioning

confidence: 99%

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Dai

Sun

Feng

et al. 2018

J Cellular Molecular Medi

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High‐grade serous ovarian carcinomas (HGSOCs) were among the tumours with an unsatisfactory outcome of immune checkpoint inhibitors (ICIs). It is imperative to develop feasible biomarker for identifying responsive candidates and guiding precise immunotherapy for HGSOC patients. Here, we analysed genomic data of patients with HGSOCs to depict their immunological phenotype of tumour microenvironment (TME) and figure out the major determinants of immunogenicity. In comparison with other solid tumours, we observed the lowest levels of PD‐L1, total mutation burden (TMB) and cytolytic molecules in HGSOCs. Surprisingly, TMB is not certainly positively related to tumour immune response as it failed to predict the response to ICIs in a considerable portion of patients in previous clinical trials. By a machine learning approach in search of biomarkers for immunotherapy implications for HGSOCs, we identified the ten most dominant factors determining the immunogenicity of HGSOCs. Interestingly, we found that BRCA1 mutated tumours presented a potent immunogenic phenotype, independent of TMB, meeting the criteria of both our dominant factors and the determinants of immunogenicity established before. Our findings provide evidence that BRCA1‐mutation may be served as a predictive biomarker in guiding ICI therapies for the patients with HGSOCs.

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Section: Resultsmentioning

confidence: 99%

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Dai

Sun

Feng

et al. 2018

J Cellular Molecular Medi

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“…We also propose that, similar to the breast cancer community, a practical and robust scoring system should be developed. 43 Additional issues requiring large-scale study which were not evaluated here include: utility of image analysis; evaluation of stromal CD8 + TILs; consistency across multiple tumor sites per patient; impact of neoadjuvant chemotherapy; 45–47 relationships between CD8 + TIL levels, HGSOC molecular subtypes, 48–50 common genetic variation, 51 and epidemiologic risk factors; 52 and evaluation of other lymphocyte subsets, such as CD4 + TILs, CD20 + TILs (B cells), tertiary lymphoid structures, and plasma cells. 10,12–14,53 Clinically, it will be important to test whether CD8 + TILs predict response to certain therapies including standard chemo- and immune therapy, as, for example, CD8 + TILs predict chemo-response in subtypes of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Goode¹,

Block²,

Kalli³

et al. 2017

JAMA Oncol

251

154

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Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors which drive infiltration will be key to unravelling outcome heterogeneity in this cancer.

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“…Pre-treatment biopsies matched with post-treatment resection specimens provide valuable opportunities for examining modulation of the immune response by chemotherapy and evaluating potential predictors of response to neoadjuvant chemotherapy. Early work suggests that TILs increase following neoadjuvant chemotherapy, both cytotoxic and regulatory T cells [208,209]. Importantly, many TILs post-neoadjuvant chemotherapy express CTLA-4, PD-1 and PD-L1 [208], and tumor cell expression of PD-L1 may also be induced by neoadjuvant chemotherapy.…”

Section: Tils In Gynecological Carcinomasmentioning

confidence: 99%

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

535

340

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC)

Abstract: In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

Cited by 139 publications

References 22 publications

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC)

Abstract: In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.

Cited by 139 publications

References 22 publications

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Potent immunogenicity in BRCA1‐mutated patients with high‐grade serous ovarian carcinoma

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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Dose-Response Association of CD8⁺ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer