Hall, M. S. | Search bioRxiv

bioRxiv2026

BCL11B targeting in tumor CD8+ T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity

Tumor infiltrating CD8+ T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low BCL11B mRNA. In line with this, ablation of Bcl11b in CD8+ TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. Bcl11b KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, Bcl11b KO CD8+ T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use. HIGHLIGHTS- Adoptive transfer of Bcl11b KO CD8+ TILs surpasses WT in tumor burden reduction - Bcl11b ablation reprograms TILs and impairs the progression to Ttex state - Bcl11b KO CD8+ T cells have elevated cytotoxicity and kill only Ag-MHCI targets - BCL11B deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1 GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/742578v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@c3b965org.highwire.dtl.DTLVardef@1c09d75org.highwire.dtl.DTLVardef@a19748org.highwire.dtl.DTLVardef@d2fd6b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Cargo-free scaffold implant recruits metastatic cancer cells via lung-mimicking myeloid cell S100A8/A9 axis

Pre-metastatic niches in distant tissue facilitate metastasis from the primary tumor. Cargo-free porous polymer scaffolds implanted in tumor-bearing mice act as synthetic metastatic niches recruiting metastasizing cancer cells. Herein, we investigated the mechanisms by which these implants attract cancer cells from circulation. Scaffolds attract cancer cells in part via S100A8/A9 secreted by Gr1+ myeloid cells in a mechanism that mimics lung metastasis. Further, cancer cells attracted to the scaffold have a lung-tropic gene expression signature regardless of their tissue of origin. The scaffold implant reduces metastasis to the lung suggesting otherwise lung-tropic cancer cells are diverted to the scaffold. The suppression of metastatic spread by the scaffold suggests this mechanism may be exploited for novel therapies, and may broadly influence the design of scaffold-based drug delivery system for anti-cancer therapy.

bioengineering↗