Functional antigen processing and presentation mechanism as a prerequisite factor of response to treatment with dendritic cell vaccines and anti-PD-1 in preclinical murine LLC1 and GL261 tumor models

Abstract

Low efficacy of cancer immunotherapy encourages the search for possible resistance mechanisms and biomarkers that would predict the outcome of immunotherapy in oncology patients. Most cancer immunotherapies act on T lymphocytes, which can specifically recognize and kill tumor cells. However, for immunotherapy-activated T lymphocytes to be able to perform these functions, proper tumor Ag processing and surface presentation by MHC-I molecule is important. Knowing the significance of Ag processing and presentation mechanism (APM) in anti-tumor immune response, we sought to evaluate how the functionality of APM affects tumor immune microenvironment and response to dendritic cell vaccines (DCV) and anti-PD-1. By comparing murine Lewis lung carcinoma LLC1 and glioma GL261 models a decreased expression of APM-related genes, such as Psmb8, Psmb9, Psmb10, Tap1, Tap2, Erap1, B2m, and low expression of surface MHC-I molecule were found in LLC1 cells. Changes in APM-related gene expression affected the ability of T lymphocytes to recognize and kill LLC1 cells, resulting in the absence of cytotoxic immune response and resistance to DCV and anti-PD-1. An emerging cytotoxic immune reaction and sensitivity to DCV and anti-PD-1 were observed in GL261 tumors where APM remained functional. This study demonstrates that one of the possible mechanisms of tumor resistance to immunotherapy is a dysfunctional APM and reveals a predictive potential of APM-related gene set expression for the personalization of dendritic cell vaccine and anti-PD-1 therapies in murine pre-treated tumors.

Keywords: Ag processing and presentation mechanism; Anti-PD-1; Dendritic cell vaccine; Experimental tumor models; Immunogenicity; Predictive biomarkers.