BCL6 promotes a stem-like CD8 ⁺ T cell program in cancer via antagonizing BLIMP1

Abstract

Overcoming CD8 + T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8 + T cell (T prog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8 + T cell (T term cell) subpopulation with potent cytotoxic functions. T prog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control T prog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific T term cell generation from T prog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of T prog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX + TCF1 + T prog cells in both LNs and tumors. BCL6 expression in CD8 + T cells was up-regulated by TGF-β–SMAD2 signaling but down-regulated by the IL-2–STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of T term cell–associated genes and induced those of T prog cell–related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the T prog cell program and greatly improved the efficacy of anti–PD-1 therapy. Thus, we identified the TGF-β–BCL6 and IL-2–BLIMP1 antagonistic pathways in regulation of antitumor CD8 + T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.

IL-2 enhances effector function but suppresses follicular localization of CD8+T cells in chronic infection

“…Maintaining a balance between self-renewal, effector function and terminal exhaustion underlying by these functional subsets is essential to sustain cytotoxic killing while restraining immunopathology at the same time (Blank et al, 2019;Hashimoto et al, 2018;Kallies et al, 2020;McLane et al, 2019). Our results, together with studies published recently (Beltra et al, 2023;Codarri Deak et al, 2022;Hashimoto et al, 2022;Liu et al, 2021;Ren et al, 2022;Sun et al, 2023) suggest that regulating the TEX and TPEX cell balance is a central role of IL-2 and the downstream STAT5-BLIMP1 axis. Importantly, IL-2 promoted the generation of CX3CR1 + effector-like TEX cells without compromising the self-renewal capacity of TPEX cells.…”

Chemotherapy synergizes with cancer vaccines and expands stem-like TCF1+CD8+ T cells

“…However, we detected a reduced expression of Ly108 in TCF1+ CD8+T cells from iCRT3-treated group, indicating the inhibitor was functional (Figure 6B). The effect of iCRT3 was further confirmed by a decreased expression of BCL6, another TCF1 transcriptional target, which is linked to the maintenance of progenitor exhausted stem-like cells 22 (Supplemental Figure 7 A-B). Remarkably, the addition of iCRT3 to CarboTaxol and the vaccines abrogated the adjuvant effect of CarboTaxol post-prime, as the proportion of CD8+IFNγ+ T cells and CD8+TNFα+ T cells 15 days after the prime was decreased as compared to the vaccines + CarboTaxol group (Figure 6C).…”

BCL6 is required for the thymic development of TCRαβ + CD8αα + intraepithelial lymphocyte lineage

“…The enlarged γδ IEL population extrinsically caused by endogenous defect of CD8αα + αβ IELs in Bcl6 fl/fl Cd4 cre mice further suggests the developmental redundancy and balance between natural IEL populations under homeostatic conditions. Recently, BCL6 has been demonstrated to play crucial roles in stemness maintenance and memory generation in conventional CD8 + T cells during chronic virus infection or under the tumor microenvironment (37)(38)(39)(40)(41)53). The outcompeted BCL6-deficient conventional CD8 + T cells found in IELs in Bcl6 fl/fl Cd4 cre + CD45.1 mixed bone marrow chimeric mice further indicates the reduced stem/memory-like function in BCL6-deficient conventional CD8αβ + αβ IELs in the presence of persistent antigen stimulation in the gut microenvironments.…”

“…In the intestinal immune system, GC B cells and T FH cells regulate the production of immunoglobulin A (IgA) and IgG to control commensal or pathogenic bacteria loads ( 34 , 35 ). BCL6 is also important in CD8 + T cells by promoting follicular cytotoxic T (T FC ) cell differentiation ( 36 ), repressing CD8 + T cells exhaustion and maintaining their stemness ( 37 – 39 ), and promoting memory generation ( 40 , 41 ) during virus infections and in the tumor microenvironment.…”