Abstract Myeloid cells represent the most abundant immune component of the tumor microenvironment, where they often assume immunosuppressive roles. Therefore, developing therapeutic strategies reinvigorating immunosuppressive myeloid cell subsets is of raising interest in oncology. We have identified CLEC-1, a member of the C-type lectin receptor (CLR) family as being expressed by myeloid cells, especially by conventional type one dendritic cells (cDC1), and by tumor-associated macrophages (TAM). However, the role of CLEC-1 in myeloid function and its mechanism of action remained to be fully elucidated. Here, we investigated the effect of CLEC-1 blockade, either by genetic deletion or by antibody targeting, on myeloid function and anti-tumor response. First, we observed that CLEC-1 genetic deletion significantly increases the survival of syngeneic tumor-bearing mice in the Hepa1.6 orthotopic model of hepatocarcinoma, as well as in the AK-7 orthotopic model of mesothelioma. Moreover, the synergy with chemotherapy treatment (cyclophosphamide, gemcitabine) in the MC38 model of colon adenocarcinoma in Clec1a deficient animals significantly enhanced complete responses. Eventually, cured mice developed a robust memory antitumor immune response against the tumor. Next, we generated anti-human CLEC-1 monoclonal antibodies (mAbs) as well as CLEC-1 humanized mice. We found that CLEC-1 targeting through mAb treatment was able to prolong mouse survival as efficiently as by CLEC-1 genetic deletion in MC38 and Hepa1.6 models. CLEC-1 blockade by genetic deletion or by different mAbs treatment profoundly impacted the tumor microenvironment: we observed an increase in the frequency of invigorated dendritic cells (DCs) and macrophages, activated and memory T cells, while frequencies of immunosuppressive myeloid cells and PD1-expressing T cells largely decreased. Mechanistically, the in vivo phagocytosis of tumor cells (Hepa1.6 and MCA101) by macrophages was enhanced in CLEC-1 deficient animals compared to WT animals. Altogether, our results demonstrate that CLEC-1 acts as a novel immune checkpoint in myeloid cells and highlight its high potential as a target for innovative immunotherapy in oncology. Citation Format: Vanessa Gauttier, Irène Baccelli, Marion Drouin, Isabelle Girault, Sabrina Pengam, Emmanuelle Wilhelm, Javier Saenz, Julien Taurelle, Emmanuel Mérieau, Bérangère Evrard, Caroline Mary, Géraldine Teppaz, Ariane Desselle, Virginie Thépénier, Nicolas Poirier, Elise Chiffoleau. CLEC-1 inhibitory myeloid checkpoint blockade enhances antitumor responses and tumor phagocytosis by macrophages [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 6358.
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