Combining intratumoral adriamycin chemotherapy, CpG, and anti-OX40 (altogether COA) improved therapeutic efficacy over the mono- or dual therapies, regressing treated and contralateral untreated 4T1 tumors. In mice, COA therapy increased tumor necrosis and T cell infiltration, expanded T cells in the tumor-draining lymph node and spleen, and decreased CD11b+ splenocytes. Splenic CD4+ and, particularly, CD8+ T cell responses were detected (via ELISpot and cytokine secretion) against 4T1-derived neoantigen peptides, which could be employed in a vaccine to elicit 4T1-specific T cell responses in vivo.
Contributed by Alex Najibi
ABSTRACT: Cancer immunotherapies, including immune checkpoint blockage and adoptive transfer of CAR-T cells, have achieved historical successes for many kinds of malignancy. However, a minority of patients survive long term over 5 years without relapse, perhaps owing to tumor heterogeneity and potent immunosuppression in the tumor microenvironment. Here, using an established mouse tumor model of triple-negative 4T1 breast cancer, we show that local immunochemotherapy triggers powerful local and systemic antitumor immunity. Paraneoplastic injection of CpG, _-OX40, and anthracycline completely eliminated both local and distant large established 4T1 breast cancer without obvious relapse. Analysis of the immune cells at tumor tissues, draining lymph nodes, and spleens revealed that the local treatment increased the infiltration of CD4(+) and CD8(+) T cells in all three tissues and inhibited the accumulation of myeloid-derived suppressor cells in the spleen in a delayed response. Most importantly, this treatment triggered systemic T cell response against 4T1 tumors and some of their neoantigen epitopes as detected by IFN-_ ELISpot and intracellular cytokine assays in splenocytes. Furthermore, T cells showed specific cytotoxic activity against 4T1 tumor cells in vitro. In general, this local immunochemotherapy provides a new approach to target highly diverse neoantigens in various types of cancers without complicated and expensive antigen identification via next-generation sequencing.