Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent Oncogenic KRAS and ERBB2 ( Her2 ) Driver Mutations
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Abstract
T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8+ T cells by class I MHC. However, CD4+ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8+ or CD4+ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non–small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4+ T cells that recognized the recurrent KRASG12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. Two different T-cell receptors (TCR) specific for KRASG12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD–specific TCR in the tumor but not nonadjacent lung. Our results showed that CD4+ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4+ neoantigen-specific T cells and elucidate their role in human antitumor immunity.
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CD8+ tumor-infiltrating lymphocytes and TCRs in CD4+ T cells specifically recognize KRAS-related mutations and can be used to engineer T cells.
“CD8+ TILs and TCRs in CD4+ T cells have been found to specifically recognize KRAS-related mutations, which can be further used to engineer T cells.604,605”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [605]
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Self-citation
- Authors
- Veatch, J. R., Jesernig, B. L., Kargl, J., Fitzgibbon, M., Lee, S. M., Baik, C., Martins, R., Houghton, A. M., & Riddell, S. R.
- Affiliations
- Fred Hutch Cancer Center (US)
- Medical University of Graz (AT)
- University of Washington (US)
- Corresponding author
- Veatch, Joshua R.
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2019-06-01
- Volume
- 7
- Issue
- 6
- Pages
- 910-922
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC6584616
- OpenAlex
- W2943013004
- Cited by
- 89
- References
- 49
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 10 · 2023: 12 · 2022: 15 · 2021: 22 · 2020: 10 · 2019: 5
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | National Institutes of HealthHHS | National Institutes of Health (NIH) (T32 T32CA009515, K12 CA076930-16A1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CD4+ T cells, neoantigens, non-small cell lung cancer, KRAS G12V mutation, driver mutations, T cell receptor, tumor-specific T cell responses, antitumor immunity, adoptive cell transfer, cancer vaccination, tumor-infiltrating T cells
- MeSH terms
- Aged, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Lymphocyte Activation, Male, Middle Aged, Mutation, Neoplasm Staging, RNA, Messenger, CD4-Positive T-Lymphocytes, Gene Expression, Lymphocytes, Tumor-Infiltrating, Proto-Oncogene Proteins p21(ras), Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Computational Biology, Cell Line, Tumor, Transcriptome
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