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Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome.

ABSTRACT: Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and peripheral blood mononuclear cells during carboplatin/paclitaxel chemotherapy. We observed that the immune contexture of EOC patients is defined by the tissue of origin, independent of exposure to chemotherapy. Summarized, draining lymph nodes were characterized by a quiescent microenvironment composed of mostly non-proliferating naïve CD4 + T cells. Circulating T cells shared phenotypic features of both lymph nodes and tumor-infiltrating immune cells. Immunologically 'hot' ovarian tumors were characterized by ICOS, GITR, and PD-1 expression on CD4 + and CD8 + cells, independent of chemotherapy. The presence of PD-1 + cells in tumors prior to, but not after, chemotherapy was associated with disease-specific survival (DSS). Accordingly, we observed high MHC-I expression in tumors prior to chemotherapy, but minimal MHC-I expression in tumors after neoadjuvant chemotherapy, even though there were no differences in the number of tumor-infiltrating lymphocytes (TIL) in both groups. We therefore speculate that the TIL influx into the chemotherapy tumor microenvironment may be a consequence of the general inflammatory nature of chemotherapy-experienced tumors. Strategies to upregulate MHC-I during or after neoadjuvant chemotherapy may thus improve treatment outcome in these patients.

SUBMITTER: Brunekreeft KL

PROVIDER: S-EPMC7458665 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome.

Brunekreeft Kim L KL Paijens Sterre T ST Wouters Maartje C A MCA Komdeur Fenne L FL Eggink Florine A FA Lubbers Joyce M JM Workel Hagma H HH Van Der Slikke Elisabeth C EC Pröpper Noor E J NEJ Leffers Ninke N Adam Julien J Pijper Harry H Plat Annechien A Kol Arjan A Nijman Hans W HW De Bruyn Marco M

Oncoimmunology 20200513 1

Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and per ...[more]

PMID: 32923120

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Project description:BackgroundA validated prognostic index for the outcome of patients with advanced high-grade serous ovarian cancer (HGSOC) undergoing neoadjuvant chemotherapy (NACT) remains elusive. To address this need, we developed an ovarian neoadjuvant chemotherapy prognostic index (ONCPI) to improve predictive accuracy.MethodsWe encompassed an analysis of the clinicopathological characteristics of patients with advanced HGSOC who were administered platinum-based NACT. Blood inflammatory composite markers were calculated and converted into binary values using optimal cutoffs. Omental hematoxylin and eosin (H&E) stained slides were selected for the assessment of chemotherapy response score (CRS), which served as a measure of NACT efficacy. Logistic regression analysis and Cox proportional hazards regression model were utilized to construct a prognostic index.ResultsMultivariate logistic analysis showed that both CRS and neutrophil-to-lymphocyte ratio (NLR) independently influenced the response to platinum-based chemotherapy. Meanwhile, Kaplan-Meier and Cox regression analysis revealed that CRS score was significantly correlated with progression-free survival (PFS) and overall survival (OS), and patients with high NLR showed poor OS. We further developed an ovarian neoadjuvant chemotherapy prognostic index (ONCPI) based on the CRS and NLR. The area under the curve (AUC) value of ONCPI was 0.771 (P < 0.001, 95% CI: 0.656-0.887) for the prediction of platinum resistance. This AUC value surpasses that of the individual NLR and CRS, which were 0.670 (P = 0.018, 95% CI: 0.547-0.793) and 0.714 (P = 0.003, 95% CI: 0.590-0.839), respectively. Moreover, survival analysis suggested that patients with ONCPI of 0 and 1 were significantly associated with improved PFS and OS.ConclusionsThe ONCPI emerges as a significant prognostic marker for predicting NACT outcome in advanced HGSOC patients and holds promise for integration into clinical practice and risk-stratified trial design.

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Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome.

Publications

Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome.

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