Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells

Ziccheddu, B.; Savid-Frontera, C.; Saralamma, V. V. G.; Gatenbee, C.; Youssfi, A. A.; Chojnacka, M.; Menges, M.; Cuadrado-Delgado, L.; Durante, M.; Mullinax, J.; Reid, K.; Miranda, J. A.; Corallo, S.; Merritt, E.; Sawyer, W.; Augello, A.; Newsam, A. D.; Chahar, D.; Amador, C.; Spiegel, J. Y.; Davila, M.; Landgren, O.; Alderuccio, J. P.; Robertson-Tessi, M.; Atkins, R.; Usmani, S.; Jain, M. D.; Anderson, A. R. A.; Maura, F.; Schatz, J. H.; Locke, F. L.

doi:10.64898/2026.10.23.761341

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bioRxiv · 10.64898/2026.10.23.761341

Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells

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Abstract

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.

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Ziccheddu, B., Savid-Frontera, C., Saralamma, V. V. G., Gatenbee, C., Youssfi, A. A., Chojnacka, M., Menges, M., Cuadrado-Delgado, L., Durante, M., Mullinax, J., Reid, K., Miranda, J. A., Corallo, S., Merritt, E., Sawyer, W., Augello, A., Newsam, A. D., Chahar, D., Amador, C., Spiegel, J. Y., Davila, M., Landgren, O., Alderuccio, J. P., Robertson-Tessi, M., Atkins, R., Usmani, S., Jain, M. D., Anderson, A. R. A., Maura, F., Schatz, J. H., Locke, F. L.. 2026-10-27. Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cells. https://doi.org/10.64898/2026.10.23.761341

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