Tumor and Host Factors Regulating Anti-tumor Immunity and Immunotherapy Efficacy

Abstract

Abstract Characterization of the and tumor microenvironments has generated a framework for identifying immunotherapeutic targets and for understanding mechanisms of efficacy versus resistance. The T cell-inflamed phenotype includes expression of chemokines, T cell markers, and a type I IFN signature, whereas the non-T cell-inflamed phenotype lacks these factors and appears to display immune exclusion. The mechanisms of immune escape are likely distinct in these two subsets, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs. Deep analysis of tumor antigen-specific T cells in the tumor microenvironment has identified additional mechanisms of immune dysfunction and new potential therapeutic targets, beyond PD-1. In contrast to the T cell-inflamed tumors, non-T cell-inflamed tumors are largely immunotherapy resistant with current approaches. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via Batf3-lineage DCs. New strategies are being developed to engage or mimic this pathway, including STING agonists, TLR agonists, and other innate immune activators. The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment in patients are being elucidated using parallel genomics platforms and include tumor-intrinsic oncogenic events, germline polymorphisms in immune regulatory genes, and the composition of the commensal microbiota. Each of these is giving rise to new therapeutic strategies to improve spontaneous immune infiltration and expand immunotherapy efficacy.