Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy

SIMPLE SUMMARY: Innovative strategies to reduce immune suppression and activate tumor-specific immunity are needed to help patients who do not respond or become resistant to immune checkpoint blockade therapies. In this study, we demonstrate that the addition of a cancer vaccine targeting a tumor-associated antigen to a checkpoint inhibitor-based immunotherapy induces greater numbers of proliferative, activated, and cytotoxic tumor-infiltrating T cells, leading to improved antitumor activity in tumors otherwise resistant to immunotherapy. Our results provide the rationale for the addition of cancer vaccines in combination immunotherapy approaches being evaluated in the clinic. ABSTRACT: Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced T(regs) and CD11b(+)Ly6G(+) myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.