Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy

Abstract

SUMMARYThe goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining intratumoral T cells with enhanced anti-tumor capabilities. However, whether therapeutic cancer vaccination and ICT achieve enhanced anti-tumor immunity by distinct or somewhat overlapping immunological mechanisms remains unclear. Considering increasing interest in combining these two types of treatment to improve efficacy rates, a better understanding of how these treatments are similar and different is needed. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) cancer vaccines with anti-PD-1, anti-CTLA-4, or anti-CTLA-4 plus anti-PD-1 combination ICT in preclinical models. We found that both NeoAg vaccines and anti-CTLA-4 and/or anti-PD-1 ICT induced robust expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was more substantial following NeoAg vaccine compared to ICT. Further, we found that NeoAg vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. Additionally, anti-CTLA-4 notably induced ICOS+Th1-like CD4 T cells expressing the transcription factor Bhlhe40 and, interestingly, when combined with anti-PD-1 a small subset of Th2-like CD4 T cells was observed. Conversely, we observed a more divergent effect on certain subsets of intratumoral macrophages induced by NeoAg vaccines as compared to ICT. Although effective NeoAg vaccines or ICT expanded M1-like iNOS+macrophages, NeoAg vaccines expanded rather than suppressed (as observed with ICT) distinct subpopulations of M2-like CX3CR1+CD206+macrophages, associated with the poly I:C adjuvant used in the vaccine. Considering the similarities and difference we identified in how NeoAg vaccines versus ICT reshaped the TME, we hypothesized that combining ICT with NeoAg vaccines would expand the therapeutic window for efficacy in these preclinical models. Indeed, we found the combination NeoAg vaccine plus ICT induced superior anti-tumor control compared to either therapy in isolation, highlighting the utility of combining these modalities to eliminate cancer.HighlightsNeoantigen vaccines utilize distinct cellular mechanisms from anti-CTLA-4 or anti-PD-1 immune checkpoint therapy.Neoantigen vaccines preferentially induce PD-1+ TCF1+ stem-like and proliferating neoantigen-specific CD8 T cellsAnti-PD-1 expands PD-1+ TCF-7-NeoAg-specific Teff/Tex, with combination anti-PD-1 + anti-CTLA-4 ICT inducing robust expansion of Bhlhe40hi PD-1+ TCF-7-NeoAg-specific Teff/Tex.Anti-CTLA-4 promotes Th1-like ICOS+ Bhlhe40+ CD4 T cells, while combination anti-CTLA-4 and anti-PD-1 ICT induces a small subset of Th2-like CD4 T cellsNeoantigen vaccines induce partially distinct intratumoral macrophage remodeling from immune checkpoint therapyNeoantigen vaccines in combination with anti-CTLA-4 or anti-PD-1 provides enhanced tumor protection equivalent to or even exceeding protection seen with combination anti-CTLA-4 and anti-PD-1