Adverse prognostic impact of regulatory T-cells in testicular diffuse large B-cell lymphoma

Abstract

Objectives: Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival.

Methods: We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8⁺ , OX40⁺ , Granzyme B⁺ , Ki-67⁺ , LAG-3⁺ , TIM-3⁺ , PD-1⁺ ), CD4⁺ T-cells (CD3⁺ , CD4⁺ , TIM-3⁺ , LAG-3⁺ ), regulatory T-cells (Tregs; CD3⁺ , CD4⁺ , FoxP3⁺ ), and T helper 1 cells (Th1; CD3⁺ , CD4⁺ , T-bet⁺ ) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome.

Results: We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8⁺ TILs were Ki-67⁺ and TIM-3⁺ CTLs, whereas the most prominent CD4⁺ TILs were FoxP3⁺ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet⁺ FoxP3⁺ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features.

Conclusions: Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.

Keywords: lymphoma; regulatory T-cell; testicular diffuse large B-cell lymphoma; tumor-infiltrating lymphocyte.