VISTA Regulates the Development of Protective Antitumor Immunity

Abstract

V-domain Ig suppressor of T cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective anti-tumor immunity. VISTA is highly expressed on myeloid cells and Foxp3+CD4+ regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mab) treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME, by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated DCs within the TME. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3+CD4+ regulatory T cells. Consequently, VISTA mab administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

“…17 Combined blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy in murine tumor models. 14 Our data indicate an involvement of both VISTA and PD-1 pathways in the immune evasion in AML, therefore combinational treatment targeting these two inhibitory pathways may lead to a successful leukemia control and improve the clinical outcome.…”

“…In multiple models of solid cancers, VISTA was only detected on leukocytes, but not on tumor cells, within the tumor microenvironment. 14 However in a recent study examining clinical samples from a large cohort of patients with gastric cancer, expression of VISTA in tumor cells was observed in a small portion (41/464, 8.8%) of patients.The expression of VISTA was exclusively cytoplasmatic in the tumor cells. 40 In our study we detected significant surface expression of VISTA on the circulating leukemia cells in peripheral blood from AML patients.…”

“…In multiple mouse models of solid tumors, VISTA blockade significantly improved anti-tumor T cell response and reduced the tumor growth. 14 Anti-human blockade antibodies for VISTA have been made available. Early phase clinical trials testing their safety and efficacy in treating patients with solid tumors are currently being implemented.…”

“…Combined inhibition of both VISTA and PD-1 pathways synergistically improves anti-tumor T cell activity. 14,17 These observations suggest a strong therapeutic potential of targeting VISTA for optimal tumor control. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients.…”

“…V-domain Ig suppressor of T-cell activation (VISTA), also designated as PD-1H, is a recently defined negative regulator mediating immune evasion in cancer 11-14 . Expression of VISTA is restricted to the hematopoietic system and high on myeloid cells 11 .…”