Characterization of immune exhaustion and suppression in the tumor microenvironment of splenic marginal zone lymphoma

The role of the tumor microenvironment (TME) and intratumoral T cells in splenic marginal zone lymphoma (sMZL) is largely unknown. In the present study, we evaluated 36 sMZL spleen specimens by single cell analysis to gain a better understanding of the TME in sMZL. Using mass cytometry (CyTOF), we observed that the TME in sMZL is distinct from that of control non-malignant reactive spleen (rSP). We found that the number of T_FH cells varied greatly in sMZL, ICOS⁺ T_FH cells were more abundant in sMZL than rSP, and T_FH cells positively correlated with increased numbers of memory B cells. T_reg cell analysis revealed that TIGIT⁺ T_reg cells are enriched in sMZL and correlate with suppression of T_H17 and T_H22 cells. Intratumoral CD8⁺ T cells were comprised of subsets of short-lived, exhausted and late-stage differentiated cells, thereby functionally impaired. We observed that T-cell exhaustion was present in sMZL and TIM-3 expression on PD-1^low cells identified cells with severe immune dysfunction. Gene expression profiling by CITE-seq analysis validated this finding. Taken together, our data suggest that the TME as a whole, and T-cell population specifically, are heterogenous in sMZL and immune exhaustion is one of the major factors impairing T-cell function.