1. Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens
- Author
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Scott Kivitz, Gal Cafri, Drew C. Deniger, Steven A. Rosenberg, Parisa Malekzadeh, Paul F. Robbins, Biman C. Paria, Rami Yossef, Mark Raffeld, Nicholas P. Restifo, Amy R. Copeland, Satyajit Ray, Maria R. Parkhurst, Robert Somerville, Sang-hyun Kim, Meghan L. Good, Zhiya Yu, Abraham Sachs, Liqiang Xi, Frank J. Lowery, and Mohammad S. Jafferji
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Cancer Research ,Lymphocyte ,Receptors, Antigen, T-Cell ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Biology ,Article ,Cell therapy ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Antigen ,Antigens, Neoplasm ,medicine ,Humans ,Receptor ,integumentary system ,T-cell receptor ,Oncogenes ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Immunotherapy ,Tumor Suppressor Protein p53 ,CD8 - Abstract
Purpose: The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens. Experimental Design: PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol. Results: T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4+ and CD8+ T cells were specific for p53R175H, p53Y220C, or p53R248W neoantigens, including a 78% reactive T-cell culture against p53R175H and HLA-A*02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen–reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation–specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens. Conclusions: PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses. See related commentary by Olivera et al., p. 1203
- Published
- 2020
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