Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.

Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes—including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex—sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

The gastrointestinal (GI) tract of poultry is densely populated with microorganisms which closely and intensively interact with the host and ingested feed. The gut microbiome benefits the host by providing nutrients from otherwise poorly utilized dietary substrates and modulating the development and function of the digestive and immune system. In return, the host provides a permissive habitat and nutrients for bacterial colonization and growth. Gut microbiome can be affected by diet, and different dietary interventions are used by poultry producers to enhance bird growth and reduce risk of enteric infection by pathogens. There also exist extensive interactions among members of the gut microbiome. A comprehensive understanding of these interactions will help develop new dietary or managerial interventions that can enhance bird growth, maximize host feed utilization, and protect birds from enteric diseases caused by pathogenic bacteria.

Smad proteins are critical intracellular mediators of the transforming growth factor-␤, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-Smads are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-Smads then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-Smad function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-Smads. MAN1, through the RNA recognition motif, associates with R-Smads but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-Smad phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGF␤, BMP2, and activin-responsive promoters. This repression of TGF␤, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-Smad regulators and defines a previously unrecognized regulatory step at the nuclear periphery.The transforming growth factor-␤ (TGF␤) 1 superfamily of cytokines, including TGF␤s, BMPs, and activins, plays important roles in the regulation of various aspects of mammalian embryogenesis and carcinogenesis. The signals initiated by these cytokines are transduced by their receptors and the downstream Smad proteins (1-5). Upon ligand binding, activin or TGF␤ receptor serine/threonine kinase phosphorylates and activates the type I receptor kinase, which then phosphorylates the downstream Smad proteins. The Smad proteins are critical mediators of TGF␤ superfamily signaling. Upon phosphorylation by the activated type I receptor kinases, the receptorassociated R-Smads (Smad2 and Smad3 for TGF␤ and activin; Smad1, Smad5, and Smad8 for BMPs) oligomerize with the common mediator Smad4, translocate into the nucleus where they interact with various transcription factors, bind to DNA, and regulate transcription of downstream genes.The expression and activity of the Smad proteins can be modulated by interaction with various cellular proteins at the plasma membrane or in the cytoplasm and nucleus (2, 6, 7). For example, Smad proteins can interact with various transcriptional co-activators on promoter DNAs to regulate the activation of TGF␤, activin, or BMP target genes (2, 6). The activity or intracellular localization of the Smads can be modulated through binding to adaptors molecules such as SARA (8), Hgs (9, 10), chaperones (11), microtubules (12), or various co-repressors such as Ski, SnoN, SNIP,. O...