Chen, Yidong

The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ–producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c + KLRG1 + effector CD8 T cells (CD11c + T E ) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c + T E cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ–producing CD11c + T E cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.

Abstract Although the Sonic hedgehog (SHH) signaling pathway has been implicated in promoting malignant phenotypes of prostate cancer, details on how it is activated and exerts its oncogenic role during prostate cancer development and progression is less clear. Here, we show that GLI3, a key SHH pathway effector, is transcriptionally upregulated during androgen deprivation and posttranslationally stabilized in prostate cancer cells by mutation of speckle-type POZ protein (SPOP). GLI3 is a substrate of SPOP-mediated proteasomal degradation in prostate cancer cells and prostate cancer driver mutations in SPOP abrogate GLI3 degradation. Functionally, GLI3 is necessary and sufficient for the growth and migration of androgen receptor (AR)–positive prostate cancer cells, particularly under androgen-depleted conditions. Importantly, we demonstrate that GLI3 physically interacts and functionally cooperates with AR to enrich an AR-dependent gene expression program leading to castration-resistant growth of xenografted prostate tumors. Finally, we identify an AR/GLI3 coregulated gene signature that is highly correlated with castration-resistant metastatic prostate cancer and predictive of disease recurrence. Together, these findings reveal that hyperactivated GLI3 promotes castration-resistant growth of prostate cancer and provide a rationale for therapeutic targeting of GLI3 in patients with castration-resistant prostate cancer (CRPC). Implications: We describe two clinically relevant mechanisms leading to hyperactivated GLI3 signaling and enhanced AR/GLI3 cross-talk, suggesting that GLI3-specific inhibitors might prove effective to block prostate cancer development or delay CRPC.

Abstract Purpose: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes. Clin Cancer Res; 22(9); 2301–10. ©2015 AACR.