Abstract
BackgroundThe efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers.MethodsWhole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material.ResultsNeoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome.ConclusionsWe have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.
Highlights
The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden
We investigated the presence of neoantigen-specific T cell responses in tumor-infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) of seven Mismatch repair (MMR)-p Colorectal cancer (CRC) patients
The neoantigen landscape of mismatch repair-proficient colorectal cancers We determined the mutational profiles of seven mismatch repair-proficient (MMR-p) and two mismatch repairdeficient (MMR-d) CRC by whole-exome and transcriptome sequencing of cancer tissues and respective normal colonic mucosa (Fig. 1a, b)
Summary
The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. Thereby, MMR-d tumors generally present with genomes carrying over 10 mutations per megabase, resulting in the expression of hundreds of proteins carrying non-synonymous mutations Their immunogenic character and sensitivity to checkpoint blockade is considered to be largely derived from the recognition of somatically mutated antigens (neoantigens) by autologous T cells [5,6,7,8], in line with the strong association between mutation burden and clinical responses to checkpoint blockade in different types of solid cancers [3, 4, 8,9,10,11]. Patients diagnosed with CMS4 CRC have worse survival than patients diagnosed with the other subtypes [13]
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