Multimodal and Spatially Resolved Profiling Identifies Distinct Patterns of T-cell Infiltration in Nodal B-cell Lymphoma Entities

T-cell-engaging immunotherapies have improved the treatment of nodal B-cell lymphoma, but responses vary highly. Future improvements of such therapies require better understanding of the variety of lymphoma-infiltrating T-cells. We employed single-cell RNA and T-cell receptor sequencing alongside quantification of surface proteins, flow cytometry and multiplexed immunofluorescence on 101 lymph nodes from healthy controls, and patients with diffuse large B-cell, mantle cell, follicular, or marginal zone lymphoma. This multimodal resource revealed entity-specific quantitative and spatial aberrations of the T-cell microenvironment. Clonal PD1+ TCF7 - but not PD1+ TCF7 + cytotoxic T-cells converged into terminally exhausted T-cells, the proportions of which were variable across entities and linked to inferior prognosis. In follicular and marginal zone lymphoma, we observed expansion of follicular helper and IKZF3+ regulatory T-cells, which were clonally related and inversely associated with tumor grading. Overall, we portray lymphoma-infiltrating T-cells with unprecedented comprehensiveness and decipher both beneficial and adverse dimensions of T-cell response. ### Competing Interest Statement C.M.S. is a scientific advisor to, has stock options in, and has received research funding from Enable Medicine, Inc. G.P.N. is a co-founder and stockholder of Akoya Biosciences, Inc. and inventor on patent US9909167 (On-slide staining by primer extension).