Buchsbaum, D. | bioRxiv Science

bioRxiv2026

Jump-starting the T cell response in established tumors

Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results. Here we show that ENT enhances CD8+ T cell responses by maintaining a progenitor-like population of CD8+ T cells that supplies activated effector T cells to tumors for prolonged periods. Surprisingly, the anti-tumor effects of ENT are only experienced when delivered during a narrow window that occurs after T cell activation and before T cell exhaustion--a window that is likely closed in most patients. However, by first "jump-starting" the T cell response using an oncolytic virus, the anti-tumor activity of ENT and PD1 blockade is restored. These data establish a general paradigm, independent of tumor type, to rationally manipulate anti-tumor immunity.

immunology↗

bioRxiv2018

The expression of class II major histocompatibility molecules on breast tumors delays T cell exhaustion, expands the T cell repertoire and slows tumor growth

The expression of major histocompatibility complex II (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we tested how MHCII expression affected anti-tumor immunity. We found that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4+ and CD8+ T cells. Additionally, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8+ T cells in tumors depended on CD4+ T cells. However, both CD4+ and CD8+ T cells eventually became exhausted, even in MHCII-expressing tumors. PD1 blockade had no impact on tumor growth, potentially because tumor cells poorly expressed PD-L1. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4+ T cells and indirectly helps the activation and expansion of CD8+ T cells, but by itself, cannot prevent T cell exhaustion.\n\nPrecisThe expression of MHCII on tumor cells augments CD4 and CD8 T cell responses, expands the TCR repertoire and delays exhaustion. Hence, strategies to induce MHCII expression may be a powerful adjuvant to immunotherapeutic regimens of solid tumors.

immunology↗