Prospective analysis of antigen-specific immunity, stem-cell antigens, and immune checkpoints in monoclonal gammopathy.

Blockade of immune checkpoints(ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunityand ICPs on the risk of malignant transformationin human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immunecomposition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immunecells in 305 patients with asymptomatic monoclonal gammopathyenrolled in S0120 under the auspices of SWOG. T-cell immunityagainst stem-cell antigen SOX2and preserved humoral responses at study entry independently correlated with reduced risk of progression to clinical myeloma. Among the ICPs analyzed, expression of programmed death-ligand 1 ( PD-L1) on tumor and infiltrating T cells correlated with increased risk of clinical malignancy, and blockade of this pathway boosted anti- SOX2 immunityin culture. These data suggest that stem-cell antigens and PD-L1may be targeted for immunoprevention of myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00900263.