NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Abstract

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

“…Recently, it has been demonstrated that LATS1/2 alterations could define a subset of MPM patients that might benefit of ICIs treatment. Indeed, MP patients harboring LAST1/2 alterations showed an increased nuclear YAP activity, associated with high PD-L1 expression and infiltrative immune signature [ 145 ]. Additionally, the tumor suppressor gene NF2 is often lost in MPM patients, and it has been correlated with compromised mediated immunity by B cells [ 145 ].…”

“…Indeed, MP patients harboring LAST1/2 alterations showed an increased nuclear YAP activity, associated with high PD-L1 expression and infiltrative immune signature [ 145 ]. Additionally, the tumor suppressor gene NF2 is often lost in MPM patients, and it has been correlated with compromised mediated immunity by B cells [ 145 ]. These findings indicate that frequently occurring MPM genetic alterations may have a role in tumor immunity and provide an early tool of biomarkers that may help to guide the management of immunotherapy in MPM patients [ 146 ].…”

Advances in Immunotherapy of Malignant Pleural Mesothelioma

“…At the same time, they observed that in MPM with low NF2 expression, a high plasma B-cell infiltrative signature predicts better overall survival. 38 A study on a unique phenotype of MPM immune microenvironment showed that p14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression) and p14/ARF-negative tumors appear to have an immune microenvironment less sensitive to immune checkpoint inhibitors. 39 …”

“…Low NF2 expression, a high plasma B-cell infiltrative signature predicts better overall survival. [ 37 , 38 ] …”

Precision Therapy for Mesothelioma: Feasibility and New Opportunities

“…Alternative approaches to target Hippo-inactivated MPMs are emerging. Preclinical studies have highlighted potential sensitivity to SRC or BCR/Abl inhibition [ 31 ]. TEAD inhibitors are currently in development and could directly disable transcriptional oncogenic signalling [ 32 ].…”