Targeting immune checkpoints of the adaptive immunity has shown great therapeutic efficacy to fight cancers, but in a limited proportion of patients. Myeloid cells represent a major immune cell type infiltrating many solid tumors, and are often associated with a poor outcome. While TAMs (mainly MDSCs and macrophages) are involved in the regulation of immune responses and in tissue repair in healthy individuals, they can be co-opted by cancer cells to exert suppressor functions, preventing action of other immune cells. In addition to their suppressor functions, TAMs can also participate in tumor growth and metastasis through several other mechanisms. SIRPalpha (SIRPa) is an immune checkpoint expressed by nearly all myeloid cells which interacts with the ubiquitous receptor CD47 and is now well described to regulate macrophage functions, including phagocytosis. Here we evaluated the impact of SIRPa signaling inhibition on tumor microenvironment and metastasis development in orthotopic tumor models in immunocompetent mice.

We first found that administration of an antagonist anti-SIRPa monoclonal antibody (mAb) in monotherapy significantly reduces tumor growth in an orthotopic mouse triple-negative mammary carcinoma (4T1) model (n=20, p<0.01) and significantly reduces lung metastasis development (p<0.05). Tumor microenvironment analysis by flow cytometry at early time-point (10 days post-treatment) revealed significant increased frequency of M1 inflammatory macrophages (including M1/M2 ratio), NK cells and both increased of intra-tumoral activated CD8+ T cells and memory CD4+ T lymphocytes. Similarly, using SIRPa mutant mice (deletion of the intracellular signaling domain) in an orthotopic mesothelioma (AK7) model, we found that absence of SIRPa signaling significantly reduces tumor growth as compared to wild-type mice (n= 8, p<0.01). Tumor microenvironment analysis by flow cytometry revealed also significant accumulation of intra-tumoral F4/80+ macrophages, CD11c+ dendritic cells, CD8+ T cells and increased CD8/MDSC ratio. Intra-tumoral CD8+ T lymphocytes significantly over-expressed activation markers (e.g. CD69) in SIRPa mutant mice. Finally, using the orthotopic B16F10 melanoma model, we found that curative treatment (initiated two weeks after tumor inoculation) with the antagonist anti-SIRPa monoclonal antibody significantly reduced tumor growth in this aggressive model (n=7, p<0.05), with two mice treated with the anti-SIRPa mAb in complete remission and two others in partial remission at the end of the study.

In conclusion, we found that inhibition of SIRPa signaling in monotherapy rewire innate and adaptive immune cells in cancer. Such straight modifications in the tumor microenvironment led to a reduction in tumor growth in different orthotopic solid tumor models and prevention of metastasis development.

Citation Format: Justine Durand, Vanessa Gauttier, Aurore Morello, Sabrina Pengam, Bernard Vanhove, Nicolas Poirier. SIRPa inhibition monotherapy leads to dramatic change in solid tumor microenvironment and prevents metastasis development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1753.