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Published on: July 28, 2010
Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer
Peter M K Westcott1, Nathan J Sacks1, Jason M Schenkel1,2,3
1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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.
Insights
Microsatellite stable colorectal cancer (CRC) has neoantigens, but low expression hinders immune response. Restoring immune priming enables T cells to control these tumors, improving immunotherapy outcomes.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune evasion is a key cancer trait, with immunotherapy effective in high tumor mutation burden (TMB) cancers.
- Low TMB cancers are often immunotherapy-resistant, and their neoantigen immunogenicity is poorly understood.
Purpose of the Study:
- To investigate the presence and impact of neoantigens in microsatellite stable (MSS) colorectal cancer (CRC).
- To determine if neoantigen expression levels influence T cell response and immunotherapy efficacy in MSS CRC.
Main Methods:
- Analysis of predicted neoantigens in MSS CRC tumors.
- Utilizing CRC organoids and mouse models to modulate neoantigen expression.
- Assessing T cell priming, dysfunction, and tumor control in response to neoantigen expression levels.
Main Results:
- All MSS CRC tumors express clonal predicted neoantigens, despite low TMB.
- Neoantigens are expressed at lower levels in MSS CRC compared to microsatellite instability (MSI) CRC.
- Low neoantigen expression impairs T cell priming and causes T cell dysfunction.
- Restoring T cell priming enables control of tumors with low neoantigen expression.
Conclusions:
- Neoantigen expression level is critical for immune evasion in MSS CRC.
- Targeting neoantigen expression or T cell priming may overcome immunotherapy resistance in low TMB cancers.
- Findings highlight a mechanism for immune evasion and a potential therapeutic strategy for MSS CRC.
