Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy
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The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such “multipronged” T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cell |
| Vol/bind | 186 |
| Udgave nummer | 16 |
| Sider (fra-til) | 3333-3349.e27 |
| Antal sider | 45 |
| ISSN | 0092-8674 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
A.K.S. is a Wellcome Senior Investigator (220295/Z/20/Z). Background methodology was funded via a Biotechnology and Biological Sciences Research Council (BB/H001085/1). C.R. A.W. V.B. P.H. S.A.E.G. S.T. A.L. and M.L. were PhD students funded by Health and Care Research Wales (A.W.), Cancer Research Wales (C.R. V.B. and P.H.), Tenovus Cancer Care (S.A.E.G.), Breast Cancer Now (S.T.), The Medical Research Council UK (A.L.), and Cancer Research UK (M.L.). Clinical trial NCT00937625 from which the TIL and patient autologous melanoma samples came from was supported by grants from Aase and Ejner Danielsens Foundation, the Danish Cancer Society, the Lundbeck Foundation, and the Capital Region of Denmark Research Foundation. G.D. B.Sz. and A.K.S. conceived the study. O.O. S.M. P.H. C.F. J.Z. C.A. M.D. and I.M.S. acquired the donor samples and clinical data. G.D. C.R. A.W. B.S. V.B. S.A.E.G. M.S.H. T.M. S.T. H.T. L.R.T. A.F. K.T. M.L. M.A. M.C. J.R.H. E.B. A.L. A.R. M.D.C. D.K.C. P.E.B. and P.R. undertook experiments and/or analyzed the data. G.D. C.R. A.W. B.Sz. and A.K.S. wrote the manuscript. The authors have patents granted and pending on T cell recognition of cancer via Melan A, BST2, and/or IMP2. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability.
Funding Information:
A.K.S. is a Wellcome Senior Investigator ( 220295/Z/20/Z ). Background methodology was funded via a Biotechnology and Biological Sciences Research Council ( BB/H001085/1 ). C.R., A.W., V.B., P.H., S.A.E.G., S.T., A.L., and M.L. were PhD students funded by Health and Care Research Wales (A.W.), Cancer Research Wales (C.R., V.B. and P.H.), Tenovus Cancer Care (S.A.E.G.), Breast Cancer Now (S.T.), The Medical Research Council UK (A.L.), and Cancer Research UK (M.L.). Clinical trial NCT00937625 from which the TIL and patient autologous melanoma samples came from was supported by grants from Aase and Ejner Danielsens Foundation , the Danish Cancer Society , the Lundbeck Foundation , and the Capital Region of Denmark Research Foundation .
Publisher Copyright:
© 2023 The Authors
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