Biology subjects

McCaw, T.

Publications and source records attributed to McCaw, T..

3 recordsLinked to original sources

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↗

bioRxiv2025

Inhibition of AXL dependent non-professional efferocytosis sensitizes pancreatic cancer to immune checkpoint blockade

AXL, a receptor tyrosine kinase, is upregulated in the majority of pancreatic adenocarcinoma (PDAC) and is associated with aggressive tumor behavior. Canonically, AXL is essential for efferocytosis, or the immunologically silent phagocytic clearance of apoptotic cells. While crucial to ensure self-tolerance, efferocytosis in cancer removes tumor antigens and dampens the antitumor response to create a pro-tumorigenic environment. Here, we show that PDAC cells co-opt the AXL pathway to act as non-professional efferocytes and clear chemotherapy induced apoptotic cells from their environment in vitro and in vivo. Inhibition of AXL with the selective inhibitor BGB324 inhibits efferocytosis and increases apoptotic cell burden, immunogenic cell death, and CD8 T cell infiltration in gemcitabine treated tumors in vivo. Single cell RNA expression analysis reveal that AXL inhibited gemcitabine treated tumors are enriched in the immunecheckpoint responsive TCF1+ CD8 T cells and respond to anti-PD1 therapy in vivo. We establish a novel ability of pancreatic cancer cells to engage in non-professional efferocytosis in response to chemotherapy. Inhibiting this response can be leveraged to sensitize this classically immune quiescent cancer to immunotherapy.

cancer biology↗

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↗