T-cell subsets within the FL microenvironment. (A) FL is characterized by a defective antitumor immune TME including amplified Treg/Tfr cells and exhausted CD4 and CD8 T cells expressing high amounts of immune checkpoint inhibitors, such as PD1, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), and reduced CD27 and CD28 costimulatory receptors. Ligands of immune checkpoint inhibitors and immunosuppressive enzymes are mainly expressed by TAMs and FDCs. However, tumor B cells play a central role in the induction of the altered immune TME, by overexpressing CCL22, inducible T-cell costimulator ligand (ICOSL), and transforming growth factor (TGFβ), involved in T-cell exhaustion and Treg amplification. FL B cells also frequently display reduced MHC I and MHC II expression, thus abrogating immune recognition by cytotoxic T cells. In addition, the cytotoxic activity of TAMs and NK cells is inhibited, particularly through CD47 and lectin-like transcript 1 (LLT1) expression by tumor B cells. (B) Tfh are expanded in FL and overexpress CD40L, IL-4, IL-21, and TNF/LT, thus contributing to tumor B-cell survival and transcriptomic plasticity. FL Tfh cells also favor B-cell–TAM cross talk, trigger CXCL12 expression in FL CAFs, and increase CCL22 expression by tumor B cells. FL Tfh could differentiate into FL Tfr that contribute to tumor immune escape. FL B cells contribute to FL Tfh amplification and reprogramming, notably by expressing CD40, ICOSL, and IL-6, and by losing herpes virus entry mediator (HVEM) expression, thus alleviating the B and T lymphocyte attenuator (BTLA)-mediated inhibitory signal on Tfh. Figure created with BioRender.com.