Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients
| Title: | Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients |
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| Authors: | Shari Pilon-Thomas; Daniel Abate-Daga; Amod A. Sarnaik; James J. Mule; Xiaoqing Yu; Patrick Innamarato; Jamie Blauvelt; Holly Branthoover; Jake Ceccarelli; TJ Langer; MacLean S. Hall; Jamie K. Teer; Sebastian Snedal; Madeline Rodriguez-Valentin; Luz Nagle; Ellen Scott; Ben Schachner; Amy M. Hall; Carolyn J. Rich; Allison D. Richards; Sean J. Yoder; Matthew S. Beatty; Cheryl A. Cox; Jane L. Messina; John E. Mullinax |
| Source: | Journal for ImmunoTherapy of Cancer, Vol 11, Iss 10 (2023) |
| Publisher Information: | BMJ Publishing Group |
| Publication Year: | 2023 |
| Collection: | Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282 |
| Description: | Background Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress.Methods We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT.Results We discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL.Conclusions Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | https://jitc.bmj.com/content/11/10/e007288.full; https://doaj.org/toc/2051-1426; https://doaj.org/article/389eec90db77472d949e719312488bf2 |
| DOI: | 10.1136/jitc-2023-007288 |
| Availability: | https://doi.org/10.1136/jitc-2023-007288; https://doaj.org/article/389eec90db77472d949e719312488bf2 |
| Accession Number: | edsbas.FC566FCB |
| Database: | BASE |