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Westcott PMK, Sacks NJ, Schenkel JM, et al. Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer. Nat Cancer. 2021;2(10):1071-1085doi: 10.1038/s43018-021-00247-z.
Westcott, P. M. K., Sacks, N. J., Schenkel, J. M., Ely, Z. A., Smith, O., Hauck, H., Jaeger, A. M., Zhang, D., Backlund, C. M., Beytagh, M. C., Patten, J. J., Elbashir, R., Eng, G., Irvine, D. J., Yilmaz, O. H., & Jacks, T. (2021). Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer. Nature cancer, 2(10), 1071-1085. https://doi.org/10.1038/s43018-021-00247-z
Westcott, Peter M K, et al. "Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer." Nature cancer vol. 2,10 (2021): 1071-1085. doi: https://doi.org/10.1038/s43018-021-00247-z
Westcott PMK, Sacks NJ, Schenkel JM, Ely ZA, Smith O, Hauck H, Jaeger AM, Zhang D, Backlund CM, Beytagh MC, Patten JJ, Elbashir R, Eng G, Irvine DJ, Yilmaz OH, Jacks T. Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer. Nat Cancer. 2021 Oct;2(10):1071-1085. doi: 10.1038/s43018-021-00247-z. Epub 2021 Sep 30. PMID: 34738089; PMCID: PMC8562866.
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Nat Cancer. 2021 Oct;2(10):1071-1085. doi: 10.1038/s43018-021-00247-z. Epub 2021 Sep 30.

Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer.

Nature cancer

Peter M K Westcott, Nathan J Sacks, Jason M Schenkel, Zackery A Ely, Olivia Smith, Haley Hauck, Alex M Jaeger, Daniel Zhang, Coralie M Backlund, Mary C Beytagh, J J Patten, Ryan Elbashir, George Eng, Darrell J Irvine, Omer H Yilmaz, Tyler Jacks

Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  2. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  3. Harvard Medical School, Boston, MA 02115, USA.
  4. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  6. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
  7. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  8. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  9. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

PMID: 34738089 PMCID: PMC8562866 DOI: 10.1038/s43018-021-00247-z

Abstract

Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB) (e.g., those with microsatellite instability (MSI)). Whether low TMB cancers, which are largely refractory to immunotherapy, harbor potentially immunogenic neoantigens remains unclear. Here, we show that tumors from all patients with microsatellite stable (MSS) colorectal cancer (CRC) express clonal predicted neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels compared to those in MSI CRC. Using a versatile platform for modulating neoantigen expression in CRC organoids and transplantation into the distal colon of mice, we show that low expression precludes productive cross priming and drives immediate T cell dysfunction. Strikingly, experimental or therapeutic rescue of priming rendered T cells capable of controlling tumors with low neoantigen expression. These findings underscore a critical role of neoantigen expression level in immune evasion and therapy response.

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