Effects of anti-VISTA mAb and its combination therapy in antitumor immunity (TUM2P.1035)

Abstract

Abstract [Purpose] V-domain Ig suppressor of T-cell activation (VISTA) is a novel immune checkpoint molecule that regulate T-cell activation. VISTA is expressed on both T cells and antigen-presenting cells. In this study, we generated a new mAb against VISTA (MIH63) and examined effects of monotherapy and combined therapy with either CTLA-4 or PD-1 blockade in murine SCCVII and CT26 tumor models. [Results] In a SCCVII tumor model, VISTA was expressed on all TIL and regional lymph node (rLN) T cells, whereas CTLA-4 was selectively induced in all CD8⁺ TIL and LN cells and PD-1 was induced on some T cells. Monotherapy with MIH63 did not clearly affect the growth of SCCVII and CT26, but significantly elevated CD8+ T cell activation assessed by CD25, IFN-g and TNF-a expression. MIH63 significantly reduced the number of CD8+ T cells. Monotherapy of CTLA-4 blockade efficiently reduced the tumor growth and a combination therapy with MIH63 further decreased the tumor growth. Consistently, MIH63 in the combination therapies enhanced CD8+ T cell activation, but decreased the ratio of CD8+ T cells. Blockade of FcγR by 2.4G2 restored the depletion of CD8+ T cells by MIH63, but not the CD8+ T cell activation. [Discussion] Our results suggest that MIH63 mainly acts as an antagonistic mAb to interfere regulatory function of VISTA, but in some part, induce CD8+ T cell-depletion via FcγR-mediated ADCC. The use of non-depleting anti-VISTA mAb may develop more effective results in the VISTA blockade.