Mechanisms Of "Peptide Alarm Therapy": Can Antiviral Memory T Cells Directly Kill Cancer Cells In An Mhc Class I-Dependent Way?

Abstract “Peptide alarm therapy” is a novel cancer immunotherapy that repurposes antiviral memory CD8+ T cells within tumors to drive antitumor immunity. After a primary infection, antigen-specific CD8+ T cells establish a surveillance program that positions T cells throughout the entire body. In particular, resident-memory CD8+ T cells (Trm) permanently reside in all tissues after primary antigen exposure and survey their immediate surroundings for possible re-exposure. In addition to normal tissue, antiviral Trm populate solid tumors. In contrast to tumor-specific T cells, intratumoral antiviral Trm are not exhausted and demonstrate potent reactivation with cognate peptide. This re-activation of Trm in tumors leads to upregulation of effector molecules and chemokines, the local recruitment of circulating immune cells, and the increased migration of dendritic cells to the tumor-draining lymph node. The intratumoral injection of peptide, and the subsequent reactivation of antiviral Trm, induces tumor growth suppression and exhibits synergy with immune checkpoint blockade, specifically PD-L1. The mechanisms driving this antitumor immune response remain uncharacterized. In this study, we have tested whether viral peptide presentation by cancer cells is necessary for the efficacy of peptide alarm therapy. A targeted knock-out of the MHC Class I allele, H-2Kb, in the B16.F10 melanoma cell line has been generated and employed in combination with the OT-I Tg CD8+ T cells, which bind the SIINFEKL:H-2Kb peptide:MHCI complex. Our data suggest that peptide presentation by cancer cells is not necessary for the reactivation of intratumoral antiviral Trm, and does not reduce tumor growth suppression in the context of peptide alarm therapy.