NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

Garcia-Agullo, J.; Santos, V.; Majem, B.; Munarriz-Panos, M.; Serrano-Ron, L.; Calvo de Mora, M.; Sanchez-Redondo, S.; Achuela, D.; Acena-Gonzalo, T.; Sentis, I.; Pascual, G.; Blanco-Aparicio, C.; Al-Shahrour, F.; Caleiras, E.; Peset, I.; Rodrigo, J. P.; Garcia-Pedrero, J. M.; Alvarez-Fernandez, M.; Saragovi, H. U.; Nogues, L.; Casanova-Acebes, M.; Aznar-Benitah, S.; Peinado, H.

doi:10.64898/2026.08.24.746602

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bioRxiv · 10.64898/2026.08.24.746602

NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

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Abstract

Immune checkpoint blockade has revolutionized cancer therapy; however, numerous tumors remain resistant by adopting cellular states that impede immune recognition. In this study, we identify the nerve growth factor receptor (NGFR) as a regulator of immune evasion in head and neck squamous cell carcinoma (HNSCC). Genetic ablation of Ngfr resulted in impaired tumor growth in immunocompetent MOC2 HNSCC, while pharmacological inhibition with THX-B reduced primary tumor growth and spontaneous metastatic dissemination. Single-cell profiling of MOC2 tumors demonstrated that Ngfr loss redirected tumor cells away from invasive EMT-like states and enhanced antigen-processing and presentation programs. This was accompanied by increased presentation of tumor antigens and expansion of effector CD8+ T-cells in vivo. Functionally, CD8+ T-cell depletion, Batf3 deficiency, and JAK1/2 inhibition restored the growth of Ngfr-deficient tumors, indicating that NGFR loss exposes tumors to CD8+ T-cell-mediated control through a JAK-associated antigen-presentation program. Notably, NGFR blockade sensitized otherwise resistant MOC2 tumors to anti-PD1 therapy, and the combination of THX-B with anti-PD1 significantly improved tumor control and survival. In human HNSCC, spatial profiling revealed that NGFR+ tumor regions exhibited reduced HLA-DR expression and limited CD3+ T-cell infiltration. Notably, an NGFR-associated antigen-presentation signature stratified survival and response in HNSCC patients undergoing immune checkpoint blockade. Interestingly, this signature was also linked to improved outcomes in melanoma patients. We also observed a significant increase in the effector CD8+ T-cell fraction in melanoma NGFR KO tumors linked to a significant decrease in tumor growth. These findings position NGFR as a regulator of tumor immune visibility and support NGFR inhibition as a strategy to enhance immunotherapy response.

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Garcia-Agullo, J., Santos, V., Majem, B., Munarriz-Panos, M., Serrano-Ron, L., Calvo de Mora, M., Sanchez-Redondo, S., Achuela, D., Acena-Gonzalo, T., Sentis, I., Pascual, G., Blanco-Aparicio, C., Al-Shahrour, F., Caleiras, E., Peset, I., Rodrigo, J. P., Garcia-Pedrero, J. M., Alvarez-Fernandez, M., Saragovi, H. U., Nogues, L., Casanova-Acebes, M., Aznar-Benitah, S., Peinado, H.. 2026-08-25. NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade. https://doi.org/10.64898/2026.08.24.746602

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