Proliferative Tumor-Infiltrating Lymphocytes' Abundance within the Microenvironment Impacts Clinical Outcome in Cutaneous B-Cell Lymphomas

Abstract

Primary cutaneous large B-cell lymphoma, leg-type (PCLBCL-LT) is the most aggressive primary cutaneous B-cell lymphoma (PCBCL). Tumor microenvironment has a crucial role in tumor development, and tumor-infiltrating lymphocytes (TILs) can be targeted by immunotherapies. We characterized TILs in 20 PCBCLs to identify the tumor microenvironment features associated with clinical outcomes. We developed a seven‒multiplex immunofluorescence panel using Opal staining and image analysis using HALO software. In PCLBCL-LT, TILs were sparsely intermingled within tumor infiltrate in contrast to those in indolent PCBCL where TILs were scattered around tumor nodule edges with variable tumor infiltration. In PCLBCL-LT, TILs were composed of CD8 and CD4, whereas CD4 was predominant in indolent PCBCL. Proliferative TILs (CD3+Ki-67+ cells) were more abundant in PCLBCL-LT (P= 0.0036) than in indolent PCBCL. In PCLBCL-LT, proliferative TILs' abundance tended to be associated with better progression-free survival. These data were confirmed in a second independent cohort of 23 cases showing that proliferative TILs were more abundant in PCLBCL-LT (P= 0.0205) and that in PCLBCL-LT, high CD3+Ki-67+ cell density was associated with better progression-free survival (P= 0.002). These distinct TILs composition and distribution among PCBCL suggest that proliferative T lymphocytes represent a good prognostic factor in PCLBCL-LT and that stimulating their functions may represent a therapeutic approach.