High-dose mIL-2/CD25 and PD-1 blockade induces local expansion of distinctive tumor-specific CD8⁺ T effector cells

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B142
Abstract ID: 4377

Presenting Author:
KATHRYN M LAPORTE , PhD Candidate at Univ. of Miami Miller Sch. of Med.

Abstract:

Most efforts on IL-2-dependent antitumor responses have focused on targeting the intermediate-affinity IL-2R to expand CD8⁺ T and NK cells while minimizing stimulation of Tregs. We have recently shown that targeting the high-affinity IL-2R on tumor-specific CD8⁺ T cells using high-dose (HD) mouse IL-2/CD25 (mIL-2/CD25) was more effective in tumor control than targeting the intermediate-affinity IL-2R and that combining HD mIL-2/CD25 with anti-PD-1 leads to even more effective tumor inhibition. Here, we investigated the mechanism of this effect by performing scRNA-sequencing of the lymphoid cells from the tumor microenvironment (TME). Cluster analysis showed that HD mIL-2/CD25 supports the development of unique CD8⁺ T effector cell subsets that are not found in the CT26 TME from control mice. These subsets exhibit a high effector program that is further amplified by anti-PD-1. TCR repertoire analysis revealed that these CD8⁺ T cells, but not Tregs, undergo robust clonal expansion. To investigate the extent that mIL-2/CD25 is active in the TME, an inhibitor of lymph node egress (FTY720) was given with HD mIL-2/CD25. CD8⁺ T cells in the TME of FTY720- and mIL-2/CD25-treated mice expanded and exhibited antitumor activity at comparable levels to mice that received only mIL-2/CD25. Together, these data suggest that mIL-2/CD25 acts within the TME to readily support the expansion of unique CD8⁺ tumor-reactive T effector cells while minimally affecting intratumoral Tregs.