Immunological targeting of the endogenous retroviral protein ERVMER34-1 in carcinomas promotes epitope spread and enhances response to PD-L1 blockade 2306293

Abstract

Endogenous retroviruses (ERVs) are remnants of germline retroviral infections that occurred over evolution and make up 5—8% of the human genome. Although ERVs are typically epigenetically silenced in healthy adult tissues, they are overexpressed in carcinomas and may represent a novel pool of immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a therapeutic target in cancer. The expression of ERVMER34-1 in healthy adult and cancer tissues was assessed by IHC. Its immunogenicity in human PBMCs was evaluated by ELISPOT assays, and the lytic ability of specific T cells was assessed by live-cell imaging assays. In addition, a rationally designed ERVMER34-1—targeted therapeutic vaccine was tested for its ability to induce tumor clearance in two murine carcinoma models, as monotherapy or in combination with immuno-oncology agents. The ERVMER34-1 protein is overexpressed in several human carcinomas while being absent in most healthy adult tissues. ERVMER34-1—specific T cells were detected in PBMCs of cancer patients but not healthy donors after overnight stimulation, yet reactive T cells expand readily from both groups after 7 days of in-vitro stimulation. These T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A rationally designed therapeutic vaccine targeting ERVMER34-1 mediated tumor control in two syngeneic murine tumors. When combined with checkpoint blockade, the vaccine induced tumor regression and promoted the expansion of neoepitope-reactive T cells, whose function was further enhanced by an FDA-approved IL-15 superagonist. The strong neoepitope response associates with an inflamed tumor microenvironment marked by increased CD8+ T-cell infiltration and improved tumor control. This study supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1, which would represent a new class of therapeutic cancer vaccine targeting ERVs. This study was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)