Neoantigen-specific CD4 + tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients

作者：MacLean Hall, Jamie K. Teer, Xiaoqing Yu, Holly Branthoover, Sebastian Snedal, Madeline Rodríguez-Valentín, Luz Nagle, Ellen Scott, Benjamin Schachner, Patrick Innamarato, Amy M. Hall, Jamie Blauvelt, Carolyn J. Rich, Allison Richards, Jake Ceccarelli, TJ Langer, Sean Yoder, Matthew Beatty, Cheryl A. Cox, Jane L. Messina, Daniel Abate‐Daga, James J. Mulé, John E. Mullinax, Amod A. Sarnaik, Shari Pilon‐Thomas · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-007288 · 被引用次数：36 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

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 t...