Abundance of VISTA-expressing CD11b cells in the absence of CD8 T cells in tumors associates with short survival in multiple myeloma
Multiple myeloma (MM) is characterized by loss of anti-tumor T cell immunity. Despite moderate successes 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 8 clinical trials (n=1654) and 1 trial-independent patient cohort (n=718) for multivariate analysis and we imaged the immune contexture of MM bone marrow tissues (n=22) via multiplex in situ stainings.
Gene expression of V-domain Ig suppressor of T cell activation (VISTA) was observed to correlate to OS, and uniquely acted as an independent prognostic marker [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 but not CD138+ tumor cells. Densities of VISTA+,CD11b+ cells or distances of these cells to CD8+ T cells or other immune cells did not differ between patients with short versus long OS. In contrast, the combination of high abundance of VISTA+,CD11b+ cells in the tumor but not stromal tissue compartment together with low abundance of CD8+ T cells in the same tissue compartment, which we termed a high VISTA-associated T cell exclusion score, significantly associated with short OS [HR: 16.6; 95% CI: 4.54-62.50;, p<0.0001].
VISTA expression is an independent prognostic factor for survival in multile myeloma. The cellular source of VISTA are CD11b myeloid cells in the tumor microenvironment and preferential localisation of these cells in the tumor over CD8 cells combined with low presence in the stromal area is associated with poor prognosis.