RT Journal Article
SR Electronic
T1 Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e004717
DO 10.1136/jitc-2022-004717
VO 10
IS 9
A1 Carsten Krieg
A1 Lukas M Weber
A1 Bruno Fosso
A1 Marinella Marzano
A1 Gary Hardiman
A1 Monica M Olcina
A1 Enric Domingo
A1 Sahar El Aidy
A1 Khalil Mallah
A1 Mark D Robinson
A1 Silvia Guglietta
YR 2022
UL http://jitc.bmj.com/content/10/9/e004717.abstract
AB 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.Data are available in a public, open access repository. Raw RNA-Seq data have been deposited at ArrayExpress under the accession number E-MTAB-8500.