Functional characterization of PD11TIM31 tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade

Abstract

In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD41 and CD81 TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell–like subgroup. Isolated PD11TIM31 TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD11 TIM31 TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-g, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD11TIM31 TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.