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

Abstract

Blockade of immune checkpoints (ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunity and ICPs on the risk of malignant transformation in human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immune composition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immune cells in 305 patients with asymptomatic monoclonal gammopathy enrolled in S0120 under the auspices of SWOG. T-cell immunity against stem-cell antigen SOX2 and 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 immunity in culture. These data suggest that stem-cell antigens and PD-L1 may be targeted for immunoprevention of myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00900263.

Figure 1

Antigen-specific immunity and risk of progression to clinical myeloma. (A) SOX2-specific T cells and risk of progression to clinical myeloma requiring therapy. (B) Virus (CEF)–specific T cells and risk of progression to clinical myeloma requiring therapy. (C) Detection of EBNA1-specific antibodies and risk of progression to clinical myeloma requiring therapy. (D) Detection of tetanus-specific antibodies and risk of progression to clinical myeloma requiring therapy. (E) Reduction in clonally uninvolved immunoglobulins and risk of progression to clinical myeloma requiring therapy.

Figure 2

ICPs and risk of progression to clinical myeloma. (A) Expression of PD-L1 on tumor cells and risk of progression to CMM requiring therapy. (B) Expression of PD-L1 on CD3⁺ T cells and risk of progression to clinical myeloma requiring therapy. (C) Expression of PD-L1 on CD4⁺ T cells and risk of progression to clinical myeloma requiring therapy. (D) Effect of PD-L1 blockade on antigen-dependent proliferation of SOX2-specific T cells in culture.