Med (New York, N.Y.) · 2026
Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.
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Lopez-Lago Miguel A, Taleb Meriem, Ningoo Mehek, Okada Tomoyo, Li Xiaoyu, Lee Hyun-Sung, Burt Bryan M, Offin Michael, Chintala Navin K, Adusumilli Prasad S
Аннотация
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.
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.