STAT1‐associated intratumoural T_H1 immunity predicts chemotherapy resistance in high‐grade serous ovarian cancer

Abstract

High‐grade serous ovarian carcinoma (HGSC) accounts for 70% of all epithelial ovarian cancers but clinical management is challenged by a lack of accurate prognostic and predictive biomarkers of chemotherapy response. This study evaluated the role of Signal Transducer and Activator of Transcription 1 (STAT1) as an independent prognostic and predictive biomarker and its correlation with intratumoural CD8+ T cells in a second independent biomarker validation study. Tumour STAT1 expression and intratumoural CD8+ T cell infiltration were assessed by immunohistochemistry as a multicentre validation study conducted on 734 chemotherapy‐naïve HGSCs. NanoString‐based profiling was performed to correlate expression of STAT1 target genes CXCL9, CXCL10 and CXCL11 with CD8A transcript expression in 143 primary tumours. Multiplexed cytokine analysis of pre‐treatment plasma from resistant and sensitive patients was performed to assess systemic levels of STAT1‐induced cytokines. STAT1 was validated as a prognostic and predictive biomarker in both univariate and multivariate models and its expression correlated significantly with intra‐epithelial CD8+ T cell infiltration in HGSC. STAT1 levels increased the prognostic and predictive value of intratumoural CD8+ T cells, confirming their synergistic role as biomarkers in HGSC. In addition, expression of STAT1 target genes (CXCL9, CXCL10 and CXCL11) correlated significantly with levels of, and CD8A transcripts from intratumoural CD8+ T cells within the resistant and sensitive tumours. Our findings provide compelling evidence that high levels of STAT1, STAT1‐induced chemokines and CD8+ T cells correlate with improved chemotherapy response in HGSC. These results identify STAT1 and its target genes as novel biomarkers of chemosensitivity in HGSC. These findings provide new translational opportunities for patient stratification for immunotherapies based on emerging biomarkers of inflammation in HGSC. An improved understanding of the role of interferon‐inducible genes will be foundational for developing immunomodulatory therapies in ovarian cancer.

PTPN 2 phosphatase deletion in T cells promotes anti‐tumour immunity and CAR T‐cell efficacy in solid tumours

“…Thus, PTPN2‐deficient CAR T cells might be especially effective against tumours such as oestrogen receptor‐negative and triple‐negative breast cancers (Shields et al , ) or lung cancers (Feng et al , ) that have low PTPN2 levels. However, it is important to note that a variety of human tumours, including for example breast, colon and ovarian cancers, express CXCL9/10/11 or do so after chemotherapy (Denkert et al , ; Sistigu et al , ; Au et al , ; Bronger et al , ; Loi et al , ; Nagarsheth et al , ; Opzoomer et al , ).…”

“…Thus, PTPN2-deficient CAR T cells might be especially effective against tumours such as oestrogen receptor-negative and triple-negative breast cancers (Shields et al, 2013) or lung cancers (Feng et al, 2017) that have low PTPN2 levels. However, it is important to note that a variety of human tumours, including for example breast, colon and ovarian cancers, express CXCL9/10/11 or do so after chemotherapy (Denkert et al, 2010;Sistigu et al, 2014;Au et al, 2016;Bronger et al, 2016;Loi et al, 2016;Nagarsheth et al, 2017;Opzoomer et al, 2019). Although it may be possible to target PTPN2 systemically with drugs to enhance T-cell and CAR T-cell responses and potentially achieve synergistic effects through the targeting of PTPN2 in both tumour cells and T cells/CAR T cells, there are several important considerations.…”

Gene networks and expression quantitative trait loci associated with platinum-based chemotherapy response in high-grade serous ovarian cancer

“…For example, the orangered4 module is composed of genes that are critical for regulation of immune response, which have been shown to play a role in chemotherapy response in HGSOC. 14,15 Genes in this module are associated with functional annotation terms including immunoglobulin receptor binding, antigen binding, B cell receptor signaling pathway, and phagocytosis. In addition, 10 of the 58 genes in this module are enriched for a common transcription factor binding site: acute myeloid leukemia 1 protein (AML1).…”

“…For example, loss of chemokines and disruptions to the IFN-γ pathway have been associated with poor treatment outcomes in HGSOC paients 13 whereas the NFκB signaling pathway and elevated expression of STAT1 were associated with increased response to platinum therapy. 14,15,16 However, these known genetic variations do not account for all of the variability in chemotherapy response among HGSOC patients and there is currently no screening method to accurately predict prognosis prior to start of chemotherapy. Thus, further studies are necessary to determine additional modulators of chemotherapy response, which can be used as biomarkers for genetic testing.…”

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

“…In our previous reports, we showed the pre-treatment immune transcriptome of tumours from platinum-resistant HGSC patients are intrinsically immunologically cold 9, 10 . We demonstrated that a non-inflamed pre-existing T helper type I tumor immune microenvironment (TIME), decreased expressions of type I interferon (IFN1) genes and STAT1 protein, low density of TILs associated with poor response to chemotherapy 10 .…”