Abstract
Follicular lymphoma (FL) is a B-cell lymphoma 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 novel 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 antigen presentation 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. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression.
Statement of significance We have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.
Competing Interest Statement
OK, MM, SI, NK, KN, AB and NF report employment by BostonGene Corporation. SA reports consultancy for Tessa Therapeutics and research funding from Seattle Genetics. SI reports research funding from Merck, Seattle Genetics, Rhizen, Affimed, Spectrum, Trillium, CrisprRx, Novartis and honoraria from Target Oncology, Curio Biosciences outside the submitted work. FV reports research funding from CRISP Therapeutics and Geron Corporation, and honoraria from i3Health, Elsevier, America Registry of Pathology, and Society of Hematology Oncology. PS reports consultancy for Roche-Genentech and research support from Astrazeneca-Acerta. SSN reports honoraria from Kite/Gilead, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, and Unum Therapeutics, research support from Kite/Gilead, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences, and Acerta, and royalties from Takeda Pharmaceuticals. LJN reports honorarium from ADC Therapeutics, Bayer, BMS/Celgene, Epizyme Genentech, Gilead/Kite, Janssen, Morphosys, Novartis, Pfizer, TG Therapeutics and research support from BMS/Celgene, Caribou Biosciences, Epizyme Genentech, IgM Biosciences, Janssen, Merck, Novartis, Pfizer, and TG Therapeutics. MRG reports research funding from Sanofi, Kite/Gilead, Abbvie and Allogene, honoraria from Tessa Therapeutics and Daiichi Sankyo, and stock ownership of KDAc Therapeutics.