Changes in the Tumor Immune Microenvironment during Disease Progression in Patients with Ovarian Cancer.

Abstract

Simple SummaryImmunotherapy has been a successful treatment for many cancers. However, no immunotherapy treatment has been approved for ovarian cancer due to low efficacy in this patient group. This study investigated the cellular and molecular changes from primary ovarian tumors, at the time of diagnosis, to recurrence, where the disease returns after surgery and chemotherapies. Here we examined the immune contexture to better understand subdued responses to immunotherapy and identify additional, potentially complimentary, therapeutic targets. Indications of the development of adaptive immune resistance during disease progression were observed, with increases in immune and stromal cell infiltration accompanied by the expression of immune suppressive markers. We observed high gene expression of the immune checkpoint genes LAG3 and HAVCR2 (TIM3) in most tumors and increased expression of the immune checkpoint genes TIGIT and CTLA4 in recurrent tumors, compared to the primaries. These markers may be potential candidates for immunotherapy targeting in ovarian cancer.Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.