Important colorectal cancer (CRC) studies in 2021, including a new standard of care for first-line treatment of MSI-H–dMMR metastatic CRC, single-cell and spatial analysis of primary tumours and investigations of diet in preclinical models of cancer initiation, have provided novel insights into the CRC immune microenvironment.
Key advances
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Pembrolizumab (an anti-PD1 monoclonal antibody) has been established as the new standard of care for first-line treatment of metastatic microsatellite-high–mismatch repair-deficient colorectal cancer4.
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Comprehensive single-cell and spatial analyses of patient samples have identified distinct multicellular immune modulatory hubs in mismatch repair-deficient and mismatch repair-proficient primary colon tumours9.
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High-fat diet can cause microbiome-dependent downregulation of MHC class II expression on LGR5+ intestinal stem cells in mice, in turn enabling immune evasion and promoting intestinal tumorigenesis10.
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References
Ganesh, K. et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 16, 361–375 (2019).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).
André, T. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383, 2207–2218 (2020).
Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).
Lenz, H.-J. et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 Study. J. Clin. Oncol. https://doi.org/10.1200/JCO.21.01015 (2021).
Ganesh, K. & Massagué, J. Targeting metastatic cancer. Nat. Med. 27, 34–44 (2021).
Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).
Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752 (2021).
Beyaz, S. et al. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell 28, 1922–1935 (2021).
Acknowledgements
K.G. is supported by NIH grants K08 CA230213, U2C CA233284 and P30 CA 008748, a Damon Runyon Clinical Investigator Award, Burroughs Wellcome Career Award for Medical Scientists, AACR NextGen Grant for Transformative Cancer Research, Josie Robertson Investigator Award and a Stand Up To Cancer Convergence Award.
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Ganesh, K. Optimizing immunotherapy for colorectal cancer. Nat Rev Gastroenterol Hepatol 19, 93–94 (2022). https://doi.org/10.1038/s41575-021-00569-4
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DOI: https://doi.org/10.1038/s41575-021-00569-4
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