Abstract 1009: Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression

Abstract

Abstract Recent evidence suggests that the efficacy of tumor immunotherapy is reliant on the signals received from the tumor microenvironment. The two prevalent cell types in the tumor microenvironment are immune cells and cancer-associated fibroblasts (CAFs). The presence of CAFs has been associated with poor survival in multiple cancer types and CAF-targeting in several experimental mouse cancer models has been shown to improve tumoral immune response and therapeutic efficacy. By conducting immunohistochemistry in 42 patient-matched primary, metastatic, and recurrent ovarian tumors, We have shown that both CAF activation and CD4+ T cell infiltration increase during cancer progression. Upon co-culturing human CAFs with CD4+ T cells, We found that CAFs physically attract CD4+ T cells. In turn, CD4+ T cells activate CAFs, as indicated by the increased ability of CAFs to contract extracellular matrix. Further experiments showed more immune suppressive T cell subtypes (Th2 and Treg cells), when co-culture activated human CAFs with CD4+ Naive T cells. A recent analysis of chemokines has shown that their expression is highly variable in primary ovarian tumors. Differential expression of chemokines in different areas of the tumor may result in a skewed distribution of immune cell types. We searched for genes that belong to the KEEG pathway ‘cytokine-cytokine receptor interaction' that are differentially expressed in the mesenchymal and mesenchymal subtype-equivalent C1 subtypes compared to all other subtypes in the TGCA and GEO datasets. Our comparison of the top 50 differentially expressed cytokine-cytokine receptor interaction genes in the mesenchymal and C1 subtypes revealed high gene signature conservation, with 32 of 50 genes being shared, including CXCL12, CXCL14, CCL11, CCL26 and KDR. Flow cytometry results showed over-expression of some cytokines in CAFs could foster CAFs into more active state, which created an immune suppressive environment by turning more T cells to Th2 and Treg subtypes. In summary, ovarian CAFs may have great impact on immune cells proliferation and differentiation, thus influence tumor progression. Citation Format: Ye Hu, Sandra Orsulic. Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1009.