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. 2020 Jul 12;9(1):1790125.
doi: 10.1080/2162402X.2020.1790125.

Colon-specific immune microenvironment regulates cancer progression versus rejection

Giulia Trimaglio  1 , Anne-Françoise Tilkin-Mariamé  2 , Virginie Feliu  3   4 , Françoise Lauzéral-Vizcaino  4   5 , Marie Tosolini  3 , Carine Valle  3 , Maha Ayyoub  3   4   5 , Olivier Neyrolles  1 , Nathalie Vergnolle  2 , Yoann Rombouts  1 , Christel Devaud  2
Affiliations

Colon-specific immune microenvironment regulates cancer progression versus rejection

Giulia Trimaglio et al. Oncoimmunology. .

Abstract

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 tissue-specific 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.

Keywords: Colorectal cancer; immune response polarization; orthotopic model.

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Figures

Figure 1.
Figure 1.
Two profiles of CRC development in immunocompetent B6 mice. a, b.
Figure 2.
Figure 2.
Rejection of MC38-fLuc tumors leads to elimination.
Figure 3.
Figure 3.
An immune-colon dependent effect generates the two CRC development profiles. a to c.
Figure 4.
Figure 4.
The immunosuppressive myeloid cell-related microenvironment is characterized in progressive CRC mice. a, b.
Figure 5.
Figure 5.
High CD8 T cells and low Treg infiltration in rejecting CRC tumors.
Figure 6.
Figure 6.
Early detection of opposing immune microenvironments in CRC tumors.
See this image and copyright information in PMC

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