2023 Theses Doctoral

Studies of Self-renewing T cells to Understand, Monitor, and Improve Responsiveness to Immune Checkpoint Blockade for Cancer

Wang, Peter Hanze

Establishing immunological T cell memory after clearance of an acute infection and sustainingongoing T cell responses against microbial or cancerous challenges requires progenitor T cells to perform the stem cell-like behavior of producing differentiated daughter cells while self-renewing their less differentiated state. In cancer patients, blockade of T cell inhibitory receptors results in intense proliferation and differentiation of progenitor T cells, which can sometimes eliminate a metastatic tumor. Despite its tremendous potential, many patients do not achieve durable anti-tumor responses from inhibitory receptor blockade.

Here I show that the response to anti-PD-1 checkpoint blockade in murine tumors is correlated with a greater frequency of self-renewing TCF1+ CD8+ T cells in the blood and tumors. Combination therapy of anti-PD-1 and an agent that promotes the stability of self-renewing TCF1+ T cells, phosphoinositide 3-kinase delta inhibitor, improves tumor control in mice and supports a heightened frequency of self-renewing TCF1+ T cells in tumors and peripheral blood. In human patients with non-small cell lung cancer, we found that a greater frequency of self-renewing T cells in the peripheral blood correlates with responsiveness to PD-1 blockade. Since the response to cancer inhibitory checkpoint blockade depends on the stem cell-like property of self-renewing TCF1+ T cells to divide and produce both differentiated and self-renewing progeny, we sought to understand the cell biological mechanism supporting discordant T cell fate outcomes in the response to cancer and chronic infection.

Using imaging cytometry and confocal microscopy, I found that dividing CD8+ T cells from draining lymph nodes and syngeneic tumors of mice had complementary subcellular compartmentalization of activating (CD3, PIP3, CD28) and inhibitory (PD1, CD73) signaling hubs. Inhibitory blockade-treated mice contained dividing progenitor cells with discordant daughter cell fates, wherein one sister undergoes differentiation while the other sister self-renews. These results provide insight into the mechanism of inhibitory blockade and potential avenues for overcoming resistance to cancer immunotherapy.