Bimodal Effect of NKG2A Blockade on Intratumoral and Systemic CD8 T Cell Response Induced by Cancer Vaccine

Simple Summary Combination therapy represents an important approach for the treatment of several types of cancer. We have previously shown that heterologous prime-boost vaccination with a protein-based cancer vaccine in combination with an oncolytic virus result in improved tumor growth control and deep remodeling of the tumor microenvironment. Here, we describe the impact of the immune-checkpoint inhibitor anti-NKG2A on tumor specific immune response induced by therapeutic vaccination in mouse tumor models. We show that NKG2A blockade has a bimodal effect on cancer vaccine induced T cell response, reducing the exhaustion of tumor infiltrating antigen-specific CD8 T cells, leading to an improved antitumoral efficacy, and at the same time influencing the establishment of systemic long-term immunological memory. Our data highlight the importance of considering the diverse impact of immunotherapy on systemic and intratumoral compartments, therefore potentially influencing the clinical outcome.Abstract Immune check-point blockade (ICB) has revitalized cancer immunotherapy, showing unprecedented efficacy despite only a narrow number of indications and with limited long-term protection. Cancer vaccines are promising combination partners for ICB to widen the patient population profiting from these treatments. Therapeutic heterologous prime-boost vaccination with KISIMATM protein vaccine and VSV-GP-TAg oncolytic virus was shown to inflame the tumor microenvironment, promoting significant infiltration of antigen-specific CD8 T cells resulting in robust antitumoral efficacy in mouse tumor models, and clinical trials are currently ongoing. Here, we report the impact of NKG2A blockade on antitumoral CD8 T cell immune response elicited by KISIMA-VSV-GP-TAg vaccination in tumor mouse models. Combination therapy significantly reduced the amount of vaccine-induced exhausted CD8 T cells infiltrating the tumor, resulting in short-term improved tumor growth control and prolonged mouse survival, while it also influenced the establishment of systemic effector memory CD8 T cell response. Taken together, these data show a compartment-dependent effect of NKG2A blockade on cancer vaccine-induced T cell immunity, increasing intratumoral T cell efficacy and attenuating the development of peripheral effector memory CD8 T cell response.