COMBINATION IMMUNOTHERAPY TARGETING IMMUNOSUPPRESSIVE SIGNALS IN THE TUMOR MICROENVIRONMENT PREVENTS CANCER PROGRESSION IN BREAST AND PANCREATIC CANCER

Abstract

Mechanisms of immune tolerance and suppression occur early at the site of developing tumors and inhibit protective responses induced by cancer vaccines, limiting their efficacy in the treatment of cancer. Combinatorial approaches to cancer immunotherapy were used to investigate the simultaneous inhibition of suppressive signals in the tumor microenvironment and induction of protective T cell responses. The inhibition of an immune checkpoint, LAG-3, in a mouse model of HER-2/neu-overexpressing mammary adenocarcinoma was found to improve CD8+ T cell function in an intrinsic manner when used in combination with a GM-CSF-secreting whole cell vaccine and Treg depletion. LAG-3 signaling also altered the phenotype of antigen-presenting cells in the tumor-draining nodes of mice. Early mechanisms of immune tolerance in a mouse model of pancreatic cancer development were characterized and targeted with Treg depletion and an attenuated Listeria vaccine targeting mutated Kras. Local, but not systemic, T cell responses were found to correlate with survival and the alteration of the tumor microenvironment towards an anti-cancer response. In both models of cancer, combination immunotherapy incorporating a vaccine and immunomodulation of the tumor microenvironment was necessary for successful immune responses that inhibited the progression of cancer.