Abstract P107: PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth

Autor: Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Veronica Komoroski, Brian O'Nuallain, Ryan Phennicie, Kevin Kauffman, Dominika Nowakowska, Joe Wahle, Steve Sazinsky, Michael Brehm, Igor Feldman, Tatiana Novobrantseva
Rok vydání: 2021
Předmět:
Zdroj: Molecular Cancer Therapeutics. 20:P107-P107
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-21-p107
Popis: Suppressive myeloid populations in the tumor microenvironment are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical studies have produced positive data for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. One new macrophage repolarizing target, PSGL-1, is expressed at high levels on immuno-suppressive TAMs and differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining a suppressive functional macrophage state. To assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model. We have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-a/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays. The PSGL-1 antibody also showed efficacy in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood. Lastly, pre-clinical efficacy of our lead anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment. The data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer. Citation Format: Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Veronica Komoroski, Brian O'Nuallain, Ryan Phennicie, Kevin Kauffman, Dominika Nowakowska, Joe Wahle, Steve Sazinsky, Michael Brehm, Igor Feldman, Tatiana Novobrantseva. PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P107.
Databáze: OpenAIRE
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