Structural basis for T cell recognition of cancer neoantigens and implications for predicting neoepitope
Roy A Mariuzza1,2, Daichao Wu3, Brian G Pierce1,2
1W.M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, United States.
Abstract:
Adoptive cell therapy (ACT) with tumor-specific T cells has been shown to mediate durable cancer regression. Tumor-specific T cells are also the basis of other therapies, notably cancer vaccines. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. The detection of neoantigens presents a major challenge to T cells because of their high structural similarity to self-antigens, and the need to avoid autoimmunity. How different a neoantigen must be from its wild-type parent for it to induce a T cell response is poorly understood. Here we review recent structural and biophysical studies of T cell receptor (TCR) recognition of shared cancer neoantigens derived from oncogenes, including p53R175H, KRASG12D, KRASG12V, HHATp8F, and PIK3CAH1047L. These studies have revealed that, in some cases, the oncogenic mutation improves antigen presentation by strengthening peptide-MHC binding. In other cases, the mutation is detected by direct interactions with TCR, or by energetically driven or other indirect strategies not requiring direct TCR contacts with the mutation. We also review antibodies designed to recognize peptide-MHC on cell surfaces (TCR-mimic antibodies) as an alternative to TCRs for targeting cancer neoantigens. Finally, we review recent computational advances in this area, including efforts to predict neoepitope immunogenicity and how these efforts may be advanced by structural information on peptide-MHC binding and peptide-MHC recognition by TCRs.
Insights
Understanding how T cells recognize cancer neoantigens is key for adoptive cell therapy (ACT) and cancer vaccines. Structural studies reveal mutations can enhance antigen presentation or be directly detected by T cell receptors (TCRs).
Area of Science:
- Oncology
- Immunology
- Structural Biology
Background:
- Adoptive cell therapy (ACT) utilizes tumor-specific T cells for cancer regression.
- T cell responses are primarily directed against neoantigens, which arise from mutations in self-antigens during cancer development.
- Distinguishing neoantigens from self-antigens is crucial to avoid autoimmunity, yet the precise requirements for T cell recognition are not fully understood.
Purpose of the Study:
- To review structural and biophysical studies on T cell receptor (TCR) recognition of shared cancer neoantigens.
- To explore mechanisms by which oncogenic mutations are detected by the immune system.
- To discuss TCR-mimic antibodies and computational advances in predicting neoepitope immunogenicity.
Main Methods:
- Review of structural and biophysical studies focusing on TCR recognition of specific oncogenic neoantigens (e.g., p53R175H, KRASG12D).
- Analysis of mechanisms including enhanced peptide-MHC binding and direct/indirect TCR interactions with mutations.
- Review of TCR-mimic antibodies and computational methods for neoepitope prediction.
Main Results:
- Oncogenic mutations can improve antigen presentation by enhancing peptide-MHC binding.
- Mutations are recognized via direct TCR interactions or indirect mechanisms, not always requiring direct contact with the mutated residue.
- TCR-mimic antibodies offer an alternative to TCRs for targeting cancer neoantigens.
Conclusions:
- Structural insights are crucial for understanding TCR-neoantigen interactions and designing effective cancer immunotherapies.
- Both direct and indirect recognition mechanisms contribute to T cell responses against cancer neoantigens.
- Advances in computational prediction, informed by structural data, hold promise for improving neoepitope selection for cancer vaccines and ACT.
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