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TIM4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

ABSTRACT: Cross-presentation of ingested tumor antigens by cells of the myeloid lineage is critical to shape anti-tumoral immune responses. However, the identity of cross-presenting macrophages, the cellular mechanism and the impact on anti-cancer CD8 T cell responses along tumor progression needs to be clarified. Here we examined the capacity of TIM4+ large peritoneal macrophages (LPM) to capture and cross-present antigens of incipient peritoneal metastasis in a model of ovarian cancer. We show that TIM4+ LPM, the most abundant myeloid population in the cavity, avidly engulf cancer cells and cross-present tumor-associated antigens, specifically at tumor inception. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake and triggers inflammatory and metabolic gene programs coupled to cytoskeletal remodeling and upregulation transcriptional signatures related to antigen processing. At the cellular levels, TIM4 is recruited with F-actin at the phagocytic cup and translocates in nascent phagosomes, controlling the kinetic of phagosomal acidification and cargo degradation. TIM4 deletion abrogates cross-presentation of tumor-associated antigens and blunts expansion of effector CD8 T cells at tumor inception. In addition, targeting tumor antigens to LPM by PS liposomes can trigger CD8 T cell activation. Together these results suggest that TIM4 enables LPMs to scan the antigenic content of incoming tumor cells to promote immune surveillance by CD8 T cells and, at defined temporal windows, may be exploited for therapeutic purposes.

ORGANISM(S): Mus musculus

PROVIDER: GSE242989 | GEO | 2023/09/17

REPOSITORIES: GEO

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Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

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TIM4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

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