Follicular Lymphoma Microenvironment Characteristics Associated with Tumor Cell Mutations and MHC Class II Expression

Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microen-vironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse tumor and immune cell populations of FL and identifi ed major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not defi ni-tive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associ-ated with signifi cant differences in the proportions and targetable immunophenotypic characteristics of T cells. This provides a classifi cation framework of the FL microenvironment in association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHCII expression. SIGNIFICANCE: We have characterized the FL-infi ltrating T cells, identifi ed cytotoxic CD4 T cells as an important component that is associated with tumor cell-intrinsic characteristics, and identifi ed sets of targetable immune checkpoints on T cells that differed from FLs with normal versus low MHC expression.

Automated summary

In this study, the tumor and immune cell populations of follicular lymphoma (FL) were characterized using single-cell RNA sequencing. Different subsets of T cells were identified, including cytotoxic CD4 T cells. Somatic mutations were found to be associated with reduced MHC expression on FL cells. The expression of MHCII genes by FL cells was correlated with significant differences in the proportions and immunophenotypic characteristics of T cells.