Harnessing tissue resident memory T cells to combat solid tumors

Abstract

Abstract The immunosuppressive tumor microenvironment is barrier to successful cancer therapies. Newly discovered tissue resident memory CD8+ T cells (TRM) function to create a potent immunostimulatory environment to protect against local reinfection. As TRM are present in abundance in nearly every tissue and can be triggered by cognate peptide alone, without adjuvant, we tested whether we could hijack infection-specific TRM in tumors to reverse the immunosuppressive tumor microenvironment and enhance existing immunotherapies. Mice with established vesicular stomatitis virus (VSV)-specific skin TRM were challenged with the transplantable B16 melanoma cell line. We find VSV-specific CD8+ T cells within established tumors and by 12 hours of cognate peptide delivery, these cells upregulate IFNγ, CD25, and granzyme B. This led to 1) a 10-fold increase in intratumoral NK cells, 2) bystander memory CD8+ T cell recruitment to the tumor, 3) tumor NK cell and CD8+ T cell activation through granzyme B upregulation and 4) DC activation in tumor draining lymph nodes through CCR7 and CD86 upregulation. Ongoing studies using transplantable and autochthonous melanoma models are testing whether TRM immunotherapy synergizes with CAR T cell and checkpoint blockade immunotherapies for eradication of recalcitrant tumors. These results demonstrate proof of principal efficacy for exploiting infection-specific TRM as a tumor immunotherapy.