Loss of Tumor Suppressor NF2 Mediates Resistance to Car T Cell and Anti-Pd-1 Therapy: Strategies to Restore Immunotherapy Sensitivity

Authors

• Miguel A Lopez-Lago
• Meriem Taleb
• Mehek Ningoo
• Tomoyo Okada
• Xiaoyu Li
• Hyun-Sung Lee
• Bryan M Burt
• Michael Offin
• Navin K Chintala
• Prasad S Adusumilli

Language

English

Publication Date

7-10-2026

Journal

Medicine

DOI

10.1016/j.medj.2026.101149

PMID

42208538

PMCID

PMC13256109

PubMedCentral® Posted Date

6-12-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Investigating the biological mechanisms of acquired resistance to immunotherapy remains a necessity for effective treatment of solid tumors.

Methods: Diffuse pleural mesothelioma (DPM) tumors, from immunocompetent and immunodeficient mouse models with acquired resistance to chimeric antigen receptor (CAR) T cell therapy were analyzed using flow cytometry, immunofluorescence, and ELISA. The interplay between genetic alterations in the cancer cell and site-specific tumor immune microenvironment (TIME) was characterized; therapies to reverse immunotherapy resistance were investigated.

Findings: Analysis of tumors with acquired resistance to CAR T cell therapy demonstrated lower expression of tumor suppressor NF2. Enforced depletion of NF2 promoted resistance to CAR T cell and anti-PD-1 therapy in DPM but not in heterotopic subcutaneous tumors. Loss of NF2 was associated with accumulation of immunosuppressive complement receptor of immunoglobulin superfamily (CRIg)+ macrophages in pleural tumors, which was dependent on tumor-secreted chemokines and retinoic acid. Ablation of chemokines or pharmacologic inhibition of retinoic acid or the Hippo pathway by use of TEAD inhibitors restored sensitivity to CAR T cell therapy. Correspondingly, in two independent cohorts of patients, DPM tumors with NF2 copy-number loss, but not mutations, were associated with higher infiltration of M2 macrophages, lower infiltration and function of CD8 T cells, and an anti-PD-1-resistant gene signature.

Conclusions: Our study uncovers a previously unknown mechanism of resistance to immunotherapy by identifying the dynamic interplay between cancer cell genetic alterations and the TIME.

Funding: This research was funded in part through the NCI UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and Department of War CA200437.

Keywords

Animals, Mice, Immunotherapy, Adoptive, Humans, Neurofibromin 2, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Immune Checkpoint Inhibitors, Mesothelioma, Drug Resistance, Neoplasm, Pleural Neoplasms, Cell Line, Tumor, Receptors, Chimeric Antigen, Immunotherapy, CAR therapy, Hippo pathway, PD-1 blockade, Pre-clinical research, TEAD inhibitors, acquired resistance, checkpoint blockade therapy, immunosupression, immunotherapy, tumor suppressor, tumor-associated macrophages

Published Open-Access

yes

Recommended Citation

Lopez-Lago, Miguel A; Taleb, Meriem; Ningoo, Mehek; et al., "Loss of Tumor Suppressor NF2 Mediates Resistance to Car T Cell and Anti-Pd-1 Therapy: Strategies to Restore Immunotherapy Sensitivity" (2026). Faculty, Staff and Students Publications. 8783.
https://digitalcommons.library.tmc.edu/baylor_docs/8783