Abstract 5125: Depletion of CCR8+ tumor Treg cells with SRF114 or anti-CCR8 therapy promotes robust antitumor activity and reshapes the tumor microenvironment toward a more pro-inflammatory milieu

Abstract FOXP3+ regulatory T (Treg) cells play a crucial role in orchestrating immune responses across several tissues, including the tumor microenvironment (TME). The dominant immune regulatory activity of Treg cells is evidenced, both clinically and preclinically, by the profound inflammatory dysregulation that arises in their absence. Leveraging controlled depletion of Treg cells in tumor tissue while sparing Treg cells in healthy tissue may be achieved through antibody-mediated targeting of the C-C chemokine receptor 8 (CCR8). CCR8 is a seven transmembrane G-coupled chemokine receptor protein whose expression is predominantly upregulated on Treg cells in several types of tumors compared with peripheral blood. Importantly, depletion of CCR8-expressing Treg cells in tumors provides a novel pathway to immunotherapy that is mechanistically independent of checkpoint inhibition (CPI). Using single-cell transcriptome and flow cytometry analyses, we evaluated the pharmacodynamic changes after treatment with anti-CCR8 antibodies to elucidate the effect of tumor Treg cell-targeting therapies on the downstream mechanisms of antitumor immunity within the TME. SRF114, a highly selective human anti-CCR8 afucosylated antibody, and an anti-mouse CCR8 antibody were utilized to preferentially deplete CCR8+ Treg cells in human CCR8 knock-in (hCCR8KI) or wild-type mice, respectively. Treatment with SRF114 or anti-mouse CCR8 antibody resulted in robust monotherapy activity in models susceptible to CPI. Moreover, pronounced monotherapy activity was also seen in checkpoint-resistant model(s), highlighting a mechanistically CPI-independent role for intratumoral Treg cell depletion to elicit potent antitumor activity. Treatment of tumor-bearing mice with anti-CCR8 antibodies resulted in a significant reduction of tumor-associated Treg cells, while peripheral Treg cells remained unchanged. Analysis of bulk tumor lysates showed that anti-CCR8 therapy elevated levels of pro-inflammatory cytokines and pro-angiogenic and chemoattracting factors. Evaluation of effector T cells demonstrated that anti-CCR8 therapy drives proliferation of CD8+ T cells and an increase in intracellular cytokine production of IFNγ, TNFα, and granzyme A. Additionally, the tumor myeloid compartment was strongly affected by anti-CCR8 therapy. Multiple myeloid cell subsets had increased levels of co-stimulatory molecules and expression of PD-L1. Altogether, selective depletion of intratumoral CCR8+ Treg cells results in robust antitumor activity by reshaping the TME toward a more pro-inflammatory milieu, providing an orthogonal approach to CPI for eliciting antitumor immunity and a strong rationale for evaluating SRF114 as a therapeutic agent for the treatment of cancer. SRF114 is currently in Phase 1 clinical studies. Citation Format: Marisella Panduro, Yue Ren, Ricard Masia, Yu Yang, Andrew C. Lake, Vito J. Palombella, Jonathan A. Hill, James F. Mohan. Depletion of CCR8+ tumor Treg cells with SRF114 or anti-CCR8 therapy promotes robust antitumor activity and reshapes the tumor microenvironment toward a more pro-inflammatory milieu. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5125.