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Published on: July 28, 2010
Neoantigen-specific immunity in low mutation burden colorectal cancers of the consensus molecular subtype 4
Jitske van den Bulk1, Els M E Verdegaal2, Dina Ruano1
1Pathology, LUMC, Postbus 9600, 2300 RC, Leiden, The Netherlands.
Background:
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. 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.
Methods:
Whole-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.
Results:
Neoantigen-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.
Conclusions:
We 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.
Insights
Neoantigen-specific T cell responses were found in mismatch repair-proficient colorectal cancers. This suggests potential for immunotherapy in CMS4 subtype colorectal cancers by targeting neoantigens and the TGF-β pathway.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Checkpoint blockade immunotherapy is effective only in a subset of colorectal cancer (CRC) patients with mismatch repair-deficient tumors.
- Neoantigen-specific T cells may exist in mismatch repair-proficient CRC, offering potential for alternative immunotherapies.
Purpose of the Study:
- To investigate the presence of autologous neoantigen-specific T cell responses in mismatch repair-proficient colorectal cancers.
- To explore the potential of these T cells for cancer immunotherapy.
Main Methods:
- Whole-exome and transcriptome sequencing of mismatch repair-proficient CRC tumors to identify neoantigens.
- Synthesis of neo-epitopes and testing for T cell recognition using tumor-infiltrating lymphocytes (TIL) and peripheral blood mononuclear cells.
- Flow cytometry sorting of TIL based on CD39 and CD103 co-expression.
Main Results:
- Neoantigen-specific T cell reactivity was detected in TIL from three mismatch repair-proficient CRC patients.
- Neoantigen-reactive TIL were identified within the CD39+CD103+ T cell subset.
- Tumors with neoantigen-reactive TIL belonged to the consensus molecular subtype 4 (CMS4), associated with TGF-β pathway activation.
Conclusions:
- Autologous T cells can exhibit neoantigen-targeted reactivity in mismatch repair-proficient CMS4 colorectal cancers.
- These findings support developing immunotherapies that enhance neoantigen-specific T cell activity and target the TGF-β pathway in this patient group.
