Immune pressure against ovarian cancer depends on antigen-specific TRM T cells

Abstract

Conventional memory T cells classically include central memory T (TCM) cells, residing in lymphoid organs, and effector memory T (TEM) cells, circulating through various tissues. Recently, a novel population of memory T cells has gained interest, namely tissue resident memory T (TRM) cells, which persist in tissues and do not recirculate. It is described that these cells reside in human tumors playing a role in tumor-specific T-cell responses. We found by flow cytometry that between 50%–80% of the CD8+ T cells in human ovarian carcinomas are CD103+CD69+TRM cells. RNA-seq of TRM and their re-circulating counterparts from 7 different human carcinomas showed a very distinctive phenotype, characterized by co-upregulation of effector (GZMB, IFNG) and exhaustion (PD-1, TIM3) markers, along with transcription factors and signaling molecules likely involved in the acquisition of the TRM phenotype. Unexpectedly, we found very little overlap between the TCR repertoire of both populations in multiple tumors, and TRM T cells consistently showed significantly higher clonality. Tumor antigen-specific TRM T cells intratumorally transferred into syngeneic mice were more effective at delaying tumor growth compared with their tumor antigen-specific recirculating counterparts. Finally, both the acquisition and the maintenance of a TRM phenotype within the CD8 T cell compartment at tumor beds are dependent on exposure to tumor cognate antigen. Together, our data indicate that TRM CD8+ T cells, but not their CD103− counterparts, represent tumor antigen-specific effector lymphocytes actively exerting anti-tumor immune pressure in the ovarian cancer microenvironment.