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Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy
- Source :
- Journal for immunotherapy of cancer, 10(9):e004717. BMC, Krieg, C, Weber, L M, Fosso, B, Marzano, M, Hardiman, G, Olcina, M M, Domingo, E, El Aidy, S, Mallah, K, Robinson, M D & Guglietta, S 2022, ' Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy ', Journal for ImmunoTherapy of Cancer, vol. 10, no. 9, e004717 . https://doi.org/10.1136/jitc-2022-004717
- Publication Year :
- 2022
-
Abstract
- Background and aimsThe role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy.MethodsWe use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry.ResultsWe found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy.ConclusionsOur findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.
- Subjects :
- Cancer Research
Anaphylatoxins
Immunology
Down-Regulation
Mice
SDG 3 - Good Health and Well-being
Tumor Microenvironment
Immunology and Allergy
Animals
Humans
Immunologic Factors
1306 Cancer Research
Immune Checkpoint Inhibitors
Basic tumor immunology
Gastrointestinal Neoplasms
Pharmacology
Inflammation
2403 Immunology
Immunity, Innate
10124 Institute of Molecular Life Sciences
Disease Models, Animal
3004 Pharmacology
Oncology
1313 Molecular Medicine
2723 Immunology and Allergy
570 Life sciences
biology
Molecular Medicine
2730 Oncology
Disease Susceptibility
Immunotherapy
Colorectal Neoplasms
Subjects
Details
- Language :
- English
- ISSN :
- 20511426
- Database :
- OpenAIRE
- Journal :
- Journal for immunotherapy of cancer, 10(9):e004717. BMC, Krieg, C, Weber, L M, Fosso, B, Marzano, M, Hardiman, G, Olcina, M M, Domingo, E, El Aidy, S, Mallah, K, Robinson, M D & Guglietta, S 2022, ' Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy ', Journal for ImmunoTherapy of Cancer, vol. 10, no. 9, e004717 . https://doi.org/10.1136/jitc-2022-004717
- Accession number :
- edsair.doi.dedup.....8cecf197684ebc7839fbbd2366deae46