Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a genome-wide CRISPR interference (CRISPRi) screen and identified androgen receptor (AR) as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in Ar also demonstrated increased tumor immunogenicity and promoted T cell–mediated tumor control. Notably, the increase in MHCI expression upon AR blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape. Significance: Immunotherapy options for immune cold tumors, like prostate cancer, are limited. We show that AR downregulates MHCI expression/antigen presentation and that AR inhibition improves T-cell responses and tumor control. This suggests that treatments combining AR inhibitors and checkpoint blockade may improve tumor immune surveillance and antitumor immunity in patients.

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies with complex phenotypic, etiological, biological, and clinical heterogeneities. Previous studies have proposed different clinically relevant subtypes of HNSCC, but little is known about its corresponding prognosis or suitable treatment strategy. Here, we identified 101 core genes from three prognostic pathways, including mTORC1 signaling, unfold protein response, and UV response UP, in 124 pairs of tumor and matched normal tissues of HNSCC. Moreover, we identified three robust subtypes associated with distinct molecular characteristics and clinical outcomes using consensus clustering based on the gene expression profiles of 944 HNSCC patients from four independent datasets. We then integrated the genomic information of The Cancer Genome Atlas (TCGA) HNSCC cohort to comprehensively evaluate the molecular features of different subtypes and screen for potentially effective therapeutic agents. Cluster 1 had more arrested oncogenic signaling, the highest immune cell infiltration, the highest immunotherapy and chemotherapeutic responsiveness, and the best prognosis. By contrast, Cluster 3 showed more activated oncogenic signaling, the lowest immune cell infiltration, the lowest immunotherapy and chemotherapy responsiveness, and the worst prognosis. Our findings corroborate the molecular diversity of HNSCC tumors and provide a novel classification strategy that may guide for prognosis and treatment allocation.

Significance: The epidemic of obesity has reached an alarming level worldwide. Understanding the etiology of obesity is important for identifying a new approach of prevention or treatment. Accumulating evidence demonstrates that the central nervous system plays a critical role in animal’s energy homeostasis. Here, we show that extended synaptotagmin (E-Syt3) is expressed in the hypothalamus and contributes to diet-induced obesity development. Whole-body or proopiomelanocortin neuron-specific deletion of E-Syt3 significantly protects mice against DIO and related metabolic disorders. Mechanistically, we show that inhibition of E-Syt3 can lead to increased hypothalamic content of α-melanocyte-stimulating hormone. Thus, our current work suggests that E-Syt3 might be a relevant target for treating obesity.