Vista blockade reprograms tumor myeloid cells and relieves adaptive resistance

Abstract

Abstract treatment. Significantly, VISTA shows broad expression in many cancer types, with enhanced expression upon development of adaptive immune checkpoint resistance. In the CT26 colon cancer model, growth of small tumors (40mm3), are retarded by anti-VISTA monotherapy, and are readily rejected following anti-CTLA4/anti-PD-L1 (CP)therapy. In contrast, very large tumors (>600mm3), are refractory to CP therapy. However, combinatorial therapy of CP with anti-VISTA leads to rejection of about half the tumors. Both in monotherapy and combination therapy the mechanisms of enhanced anti-tumor immunity were investigated using scRNAseq, multiplex image analysis and flow cytometry of the tumor immune infiltrate. In both treatment models, anti-VISTA upregulated stimulated myeloid antigen-presentation pathways and reduced myeloid mediated suppression. Multi-spectral imaging revealed an anti-VISTA stimulated increase in contacts between CD8+ T cells and myeloid cells, further supporting the notion of increased antigen presentation upon anti-VISTA treatment. Transcriptional analysis of antigen-specific CD8 T cells showed that anti-VISTA therapy induced T cell pathways highly distinct from the anti-exhaustion effects of CP. These data suggest the non-redundancy of CP and anti-VISTA treatment, and support the use of these treatments in combination to overcome the adaptive resistance seen in contemporary treatments involving PD-1 and/or CTLA-4. Research was supported by NIH grants R01AR070760 (R.J.N.), R01CA214062 (R.J.N.), and 1R21CA227996 (C.C.) and the Cancer Prevention Research Institute of Texas (CPRIT) (RR180061 to C.C.). C.C. is a CPRIT Scholar in Cancer Research.