The C5a/C5aR1 axis promotes migration of tolerogenic dendritic cells to lymph nodes, impairing the anticancer immune response.

IF 8.1 1区 医学 Q1 IMMUNOLOGY Cancer immunology research Pub Date : 2024-12-12 DOI:10.1158/2326-6066.CIR-24-0250
Yaiza Senent, Ana Remírez, David Repáraz, Diana Llopiz, Daiana P Celias, Cristina Sainz, Rodrigo Entrialgo-Cadierno, Lucia Suarez, Ana Rouzaut, Diego Alignani, Beatriz Tavira, John D Lambris, Trent M Woodruff, Carlos E de Andrea, Brian Ruffell, Pablo Sarobe, Daniel Ajona, Ruben Pio
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Abstract

The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment (TME) and promotes tumor progression remain unclear. In this study, we investigated the expression and function of complement C5a receptor 1 (C5aR1) in human and mouse cancer-associated dendritic cells (DCs). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared to DCs from blood or spleen. C5aR1 expression was restricted to type 2 conventional DCs (cDC2) and monocyte-derived DCs (moDCs), which displayed a tolerogenic phenotype capable of inhibiting T-cell activation and promoting tumor growth. C5aR1 engagement in DCs drove their migration from tumors to tumor-draining lymph nodes, where C5a levels were higher. We used this knowledge to optimize an anticancer therapy aimed at enhancing DC activity. In three syngeneic tumor models, C5aR1 inhibition significantly enhanced the efficacy of poly I:C, a Toll-like receptor 3 (TLR3) agonist, in combination with PD-1/PD-L1 blockade. The contribution of C5aR1 inhibition to the antitumor activity of the combination treatment relied on type 1 conventional DCs (cDC1s) and antigen-specific CD8+ T cells, required lymphocyte egress from secondary lymphoid organs, and was associated with an increase in interferon gamma (IFNγ) signaling. In conclusion, our study highlights the importance of the C5a/C5aR1 axis in the biology of cancer-associated DCs and provides compelling evidence for the therapeutic potential of modulating the complement system to enhance DC-mediated immune responses against tumors.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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