V-Domain Ig Suppressor of T Cell Activation (VISTA) Expression Is an Independent Prognostic Factor in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma (MM) is characterized by loss of anti-tumor T-cell immunity. The precise mechanisms by which malignant plasma cells escape T-cell immunity are unknown, although upregulation of checkpoint molecules is seen in progressive disease. The aim of our study was to investigate mechanisms of escape from T-cell immunity. We observed that the expression of V-domain Ig suppressor of T cell activation (VISTA) in the tumor microenvironment is an independent prognostic factor for survival in MM and its major cellular source is tumor infiltrating CD11B+ cells. The combination of high VISTA expression in the tumor combined with low infiltration of CD8+ cells compared to the surrounding stromal tissue is significantly associated with poor survival. These finding have identified VISTA as an interesting target for inhibition to circumvent escape of T-cell immunity. ABSTRACT: Multiple myeloma (MM) is characterized by loss of anti-tumor T cell immunity. Despite moderate success of treatment with anti-PD1 antibodies, effective treatment is still challenged by poor T cell-mediated control of MM. To better enable identification of shortcomings in T-cell immunity that relate to overall survival (OS), we interrogated transcriptomic data of bone marrow samples from eight clinical trials (n = 1654) and one trial-independent patient cohort (n = 718) for multivariate analysis. Gene expression of V-domain Ig suppressor of T cell activation (VISTA) was observed to correlate to OS [hazard ratio (HR): 0.72; 95% CI: 0.61–0.83; p = 0.005]. Upon imaging the immune contexture of MM bone marrow tissues (n = 22) via multiplex in situ stainings, we demonstrated that VISTA was expressed predominantly by CD11b+ myeloid cells. The combination of abundance of VISTA+, CD11b+ cells in the tumor but not stromal tissue together with low presence of CD8+ T cells in the same tissue compartment, termed a high VISTA-associated T cell exclusion score, was significantly associated with short OS [HR: 16.6; 95% CI: 4.54–62.50; p < 0.0001]. Taken together, the prognostic value of a combined score of VISTA+, CD11b+ and CD8+ cells in the tumor compartment could potentially be utilized to guide stratification of MM patients for immune therapies.