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

Jacks and colleagues demonstrate the effects of neoantigen expression level on T-cell priming and immune surveillance during tumor development and progression and explore implications for immunotherapies, using in vivo models of colorectal cancer. 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) (for example, those with microsatellite instability). 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 colorectal cancer express clonal predicted neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels compared to those in colorectal cancer with microsatellite instability. Using a versatile platform for modulating neoantigen expression in colorectal cancer organoids and transplantation into the distal colon of mice, we show that low expression precludes productive cross-priming and drives immediate T-cell dysfunction. Notably, 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.

Automated summary

The study reveals that despite low TMB, tumors from patients with microsatellite stable colorectal cancer still express predicted neoantigens, although at lower levels compared to those in colorectal cancer with microsatellite instability. Low expression of neoantigens may lead to immediate T-cell dysfunction, but it can be controlled by restoring priming in tumors with low neoantigen expression.