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

Guangchun Han, Qing Deng, Mario L. Marques-Piubelli, Enyu Dai, Minghao Dang, Man Chun John, Xubin Li, Haopeng Yang, Jared Henderson, Olga Kudryashova, Mark Meerson, Sergey Isaev, Nikita Kotlov, Krystle J. Nomie, Alexander Bagaev, Edwin R. Parra, Luisa M. Solis Soto, Simrit Parmar, Fredrick B. Hagemeister, Sairah Ahmed, Swaminathan P. Iyer, Felipe Samaniego, Raphael Steiner, Luis Fayad, Hun Lee, Nathan H. Fowler, Christopher R. Flowers, Paolo Strati, Jason R. Westin, Sattva S. Neelapu, Loretta J. Nastoupil, Francisco Vega, Linghua Wang, Michael R. Green

Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T-cells. This provides a classification framework of the FL microenvironment, their association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression.