The C5a/C5aR1 Axis Promotes Migration of Tolerogenic Dendritic Cells to Lymph Nodes, Impairing the Anticancer Immune Response
The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment 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 (DC). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared with DCs from the blood or spleen. C5aR1 expression was restricted to type 2 conventional DCs and monocyte-derived DCs, 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 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 and antigen-specific CD8+ T cells, required lymphocyte egress from secondary lymphoid organs, and was associated with an increase in 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.
Authors
- Daiana P. Celias (ORCID: https://orcid.org/0000-0002-5122-6718)
- Daniel Ajona (ORCID: https://orcid.org/0000-0001-5517-9165)
- Yaiza Senent (ORCID: https://orcid.org/0000-0002-0352-901X)
- Brian Ruffell (ORCID: https://orcid.org/0000-0002-3846-6872)
- Diego Alignani (ORCID: https://orcid.org/0000-0003-0241-1375)
- Diana Llópiz (ORCID: https://orcid.org/0000-0002-7111-9303)
- Carlos E. de Andrea (ORCID: https://orcid.org/0000-0002-7628-8050)
- Rubén Pı́o (ORCID: https://orcid.org/0000-0002-6831-6111)
- Lucía Suárez (ORCID: https://orcid.org/0000-0003-2087-9561)
- Trent M. Woodruff (ORCID: https://orcid.org/0000-0003-1382-911X)
- David Repáraz (ORCID: https://orcid.org/0000-0003-2706-6870)
- Ana Rouzaut (ORCID: https://orcid.org/0000-0003-3226-9162)
- Pablo Sarobe (ORCID: https://orcid.org/0000-0003-0503-7905)
- John D. Lambris (ORCID: https://orcid.org/0000-0002-9370-5776)
- Cristina Sainz (ORCID: https://orcid.org/0000-0002-1826-0930)
- Beatriz Tavira (ORCID: https://orcid.org/0000-0002-5986-6998)
- Rodrigo Entrialgo‐Cadierno (ORCID: https://orcid.org/0000-0001-9682-6971)
- Ana Remírez
Institutions
- The University of Queensland (AU)
- Moffitt Cancer Center (US)
- Navarre Institute of Health Research (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Clinica Universidad de Navarra (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University of Pennsylvania (US)
- University of Pamplona (CO)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2024-12-12
- DOI
- https://doi.org/10.1158/2326-6066.cir-24-0250
- Citations
- 14
- Primary Topic
- Complement system in diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Fundación Ramón Areces
- Fundación Científica Asociación Española Contra el Cáncer
- Universidad de Navarra
- Ministerio de Ciencia e Innovación
- Centro de Investigación Biomédica en Red de Cáncer
- Gobierno de Navarra
- Medical Research Council
- National Health and Medical Research Council
- European Regional Development Fund