Colon-specific immune microenvironment regulates cancer progression versus rejection
Résumé
Immunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset of
patients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissuespecific
factors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironment
shapes the immune response to CRC is needed to identify mechanisms of resistance to
immunotherapies and guide the development of novel therapeutics.
In an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescence
imaging and the immune signatures were assessed at a transcriptional level using NanoString and at
a cellular level by flow cytometry. Despite initial tumor growth in all mice, only 25% to 35% of mice
developed a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor.
No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injected
in non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumors
exhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernible
shortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting mice
presented an early inflammatory response and an antitumor microenvironment enriched in CD8+ T cells.
Taken together, our data demonstrate the role of the colon microenvironment in regulating the
balance between anti or protumor immune responses. While emphasizing the relevance of the CRC
orthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancer
response to immunotherapy.
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