Tcf-1 protects anti-tumor TCR-engineered CD8+ T-cells from GzmB mediated self-destruction

Abstract

Background T-cell longevity is undermined by antigen-driven differentiation programs that render cells prone to attrition through several mechanisms. CD8 + T cells that express the Tcf-1 transcription factor have undergone limited differentiation and exhibit stem-cell-like replenishment functions that facilitate persistence. We engineered human CD8 + T cells to constitutively express Tcf-1 and a TCR specific for the NY-ESO-1 cancer-associated antigen. Co-engineered cells were assessed for their potential for adoptive cellular immunotherapy. Methods Tcf-1 mRNA encoding TCF-1B and TCF-1E isoforms, along with GzmB expression were assessed in CD62L + CD57 − , CD62L − CD57 − , and CD62L − CD57 + CD8 + T cells derived from normal donor lymphocytes. The impact of stable Tcf-1B expression on CD8 + T-cell phenotype, anti-tumor activity, and cell-cycle activity was assessed in vitro and in an in vivo tumor xenograft model. Results TCF-1B and TCF-1E were dynamically regulated during self-renewal, with progeny of recently activated naïve T cells more enriched for TCF-1B mRNA. Constitutive TCF-1B expression improved the survival of TCR-engineered CD8 + T cells upon engagement with tumor cells. Tcf-1B prohibited the acquisition of a GzmB High state, and protected T cells from apoptosis associated with elicitation of effector function, and promoted stem cell-like characteristics. Conclusions Tcf-1 protects TCR-engineered CD8 + T cells from activation induced cell death by restricting GzmB expression. Our study presents constitutive Tcf-1B expression as a potential means to impart therapeutic T cells with attributes of persistence for durable anti-tumor activity. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-022-03197-2.

TET2 regulates early and late transitions in exhausted CD8+T-cell differentiation and limits CAR T-cell function

“…6D ). In line with GSEA results, chronic stimulation led to an increase in the proportion of CD8 + TET2-TRAC-CAR19 cells expressing the progenitor-associated TF TCF1 ( 60 ) and a decrease in the proportion of cells expressing the terminal differentiation-associated effector molecule granzyme B ( 61 ) compared to TRAC-CAR19 control cells ( Fig. 6E, fig.…”

BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control

“…Of note, although the majority of the FR-B 2/15 T cells that accumulated in the peritoneal TME were CD8+TALs, we also noted a modest increase in the frequency of FR-B 2/15 CD4+TALs compared with FR-B 2/7 CD4+TALs, suggesting IL-2/IL-15 preconditioning can improve the accumulation/persistence of both FR-B T cell subsets. While IL-2/IL-15 preconditioning produced stem-like FR-B T cells with a predominantly TCF-1+CD39–CD69– phenotype and improved persistence, we also recently reported on engineering T cells to stably express TCF-1 to enhance T-cell persistence 37 and this approach could be incorporated when generating BiTE-T cells. Importantly, unlike conventional ACT approaches (eg, engineering tumor reactive CAR-T or TCR-T cells) where therapeutic failure can stem from limited tumor infiltration following T-cell infusion, the capacity of BiTE-T cells to mediate tumor attack from remote location(s) outside of solid tumors suggests strategies for generating durable responses may differ among these approaches.…”

Hub gene mining and immune microenvironment analysis of autophagy in rheumatoid arthritis

“…As a serine protease, GZMB is expressed by cytotoxic T lymphocytes and NK cells. Many studies have indicated a signi cant upregulation of GZMB in RA, and its expression is associated with the occurrence and progression of RA [43] . It is worth mentioning that GZMB has certain functions in tumor immune in ltration such as skin cutaneous melanoma and colorectal cancer [44,45] .…”