Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy
Background and aims The 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/9/e004717.full |
| _version_ | 1798028036003594240 |
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| author | Enric Domingo Sahar El Aidy Gary Hardiman Carsten Krieg Lukas M Weber Bruno Fosso Marinella Marzano Monica M Olcina Khalil Mallah Mark D Robinson Silvia Guglietta |
| author_facet | Enric Domingo Sahar El Aidy Gary Hardiman Carsten Krieg Lukas M Weber Bruno Fosso Marinella Marzano Monica M Olcina Khalil Mallah Mark D Robinson Silvia Guglietta |
| author_sort | Enric Domingo |
| collection | DOAJ |
| description | Background and aims The 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.Methods We 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.Results We 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.Conclusions Our 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. |
| first_indexed | 2024-04-11T19:02:30Z |
| format | Article |
| id | doaj.art-fc97c007bd8c47ffbf5e758117697cc1 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-11T19:02:30Z |
| publishDate | 2022-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-fc97c007bd8c47ffbf5e758117697cc12022-12-22T04:08:00ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-09-0110910.1136/jitc-2022-004717Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapyEnric Domingo0Sahar El Aidy1Gary Hardiman2Carsten Krieg3Lukas M Weber4Bruno Fosso5Marinella Marzano6Monica M Olcina7Khalil Mallah8Mark D Robinson9Silvia Guglietta10Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK4Laboratory of Microbiology and Host Microbe Interactomics Group, Wageningen University, Wageningen, The NetherlandsSchool of Biological Sciences, Institute for Global Food Security, Queen`s University Belfast, Belfast, UKDepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USAInstitute of Molecular Life Sciences, University of Zurich, Zurich, SwitzerlandInstitute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, ItalyInstitute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, ItalyInstitute of Radiation Oncology, Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UKDepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USAInstitute of Molecular Life Sciences, University of Zurich, Zurich, SwitzerlandHollings Cancer Center Charleston, Medical University of South Carolina, Charleston, South Carolina, USABackground and aims The 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.Methods We 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.Results We 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.Conclusions Our 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.https://jitc.bmj.com/content/10/9/e004717.full |
| spellingShingle | Enric Domingo Sahar El Aidy Gary Hardiman Carsten Krieg Lukas M Weber Bruno Fosso Marinella Marzano Monica M Olcina Khalil Mallah Mark D Robinson Silvia Guglietta Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| title_full | Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| title_fullStr | Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| title_full_unstemmed | Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| title_short | Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| title_sort | complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy |
| url | https://jitc.bmj.com/content/10/9/e004717.full |
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