Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells
CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy induces durable remissions in a subset of patients with relapsed or refractory large B-cell lymphoma; however, most patients fail to respond or eventually relapse. By integrating whole-genome and transcriptome profiling of 54 patients with functional assays, syngeneic models, and mathematical modeling, we demonstrate that durable CAR-T efficacy requires cooperation between CAR-T cells and endogenous CD8⁺ (eCD8) T cells recruited to join the attack on malignant cells. Tumors with biallelic loss of MHC class I or CD58 exhibited high genomic complexity, increased neoantigen burden, and resistance to CAR-T therapy. MHC-I-deficient lymphomas showed suboptimal response in immunocompetent hosts compared to wild type. Importantly, sustained responses in mice occurred only in the presence of eCD8 cells, whereas all CD8⁺-depleted mice relapsed after initial CAR-T-mediated tumor regression. Patients and murine ELISPOT assays confirmed enhanced endogenous T-cell activation post-CAR-T. These findings reveal that CAR-T therapy functions not only as a cytotoxic modality but also as a catalyst for endogenous anti-tumor immunity.
Authors
- Michael David Jain (ORCID: https://orcid.org/0000-0002-7789-1257)
- Saad Z. Usmani (ORCID: https://orcid.org/0000-0002-5484-8731)
- Frederick Lundry Locke (ORCID: https://orcid.org/0000-0001-9063-6691)
- Austin Daniel Newsam (ORCID: https://orcid.org/0000-0002-8926-6539)
- Reginald M. Atkins (ORCID: https://orcid.org/0009-0007-0104-7344)
- Monika Chojnacka (ORCID: https://orcid.org/0000-0001-7176-6108)
- Dhanvantri Chahar (ORCID: https://orcid.org/0000-0002-7623-7018)
- John E. Mullinax (ORCID: https://orcid.org/0000-0002-9596-6785)
- Marco L. Davila (ORCID: https://orcid.org/0000-0002-6270-3065)
- Jay Y. Spiegel (ORCID: https://orcid.org/0000-0001-6491-0044)
- Bachisio Ziccheddu (ORCID: https://orcid.org/0000-0002-2746-0053)
- Salvatore Corallo (ORCID: https://orcid.org/0000-0002-6672-0233)
- Alexander R.A. Anderson (ORCID: https://orcid.org/0000-0002-2536-4383)
- Michael A. Durante (ORCID: https://orcid.org/0000-0003-3137-6847)
- Mark Robertson‐Tessi (ORCID: https://orcid.org/0000-0003-0143-9587)
- Meghan A. Menges (ORCID: https://orcid.org/0009-0007-7446-9492)
- Juan Pablo Alderuccio (ORCID: https://orcid.org/0000-0002-2690-3377)
- Ola Landgren (ORCID: https://orcid.org/0000-0001-6485-4839)
- Constanza Savid-Frontera (ORCID: https://orcid.org/0000-0001-8614-3528)
- Francesco Maura (ORCID: https://orcid.org/0000-0002-5017-1620)
- Abdessamad A. Youssfi
- Catalina C Amador
- W Greg Sawyer
- Luis Cuadrado-Delgado
- Anthony Augello
- Emily Merritt
- Keyla Reid
- Venu V.G. Saralamma
- Chandler Gatenbee
- Jonathan H. Schatz
- Julieta Abraham Miranda
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Moffitt Cancer Center (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-10-27
- DOI
- https://doi.org/10.64898/2026.10.23.761341
- Primary Topic
- CAR-T cell therapy research
- Type
- preprint
Funders
- Memorial Sloan-Kettering Cancer Center
- Sylvester Comprehensive Cancer Center, University of Miami Health Systems
- National Cancer Institute