• Clay Navarro posted an update 6 months ago

    Mucosal Associated Invariant T (MAIT) cells are evolutionary conserved innate-like T cells able to recognize bacterial and fungal ligands derived from vitamin B biosynthesis. These cells are particularly present in liver and blood but also populate mucosal sites including skin, oral, intestinal, respiratory, and urogenital tracts that are in contact with the environment and microbiota of their host. Growing evidence suggests important involvement of MAIT cells in safeguarding the mucosa against external microbial threats. Simultaneously, mucosal MAIT cells have been implicated in immune and inflammatory pathologies affecting these organs. Here, we review the specificities of mucosal MAIT cells, their functions in the protection and maintenance of mucosal barriers, and their interactions with other mucosal cells.Gut-associated lymphoid tissues (GALT) are the key antigen sampling and adaptive immune inductive sites within the intestinal wall. Human GALT includes the multi-follicular Peyer’s patches of the ileum, the vermiform appendix, and the numerous isolated lymphoid follicles (ILF) which are distributed along the length of the intestine. Our current understanding of GALT diversity and function derives primarily from studies in mice, and the relevance of many of these findings to human GALT remains unclear. Here we review our current understanding of human GALT diversity, structure, and composition as well as their potential for regulating intestinal immune responses during homeostasis and inflammatory bowel disease (IBD). Finally, we outline some key remaining questions regarding human GALT, the answers to which will advance our understanding of intestinal immune responses and provide potential opportunities to improve the treatment of intestinal diseases.Aggressiveness of carcinomas is linked with tumor recruitment of adipose stromal cells (ASC), which is increased in obesity. ASC promote cancer through molecular pathways not fully understood. Here, we demonstrate that epithelial-mesenchymal transition (EMT) in prostate tumors is promoted by obesity and suppressed upon pharmacological ASC depletion in HiMyc mice, a spontaneous genetic model of prostate cancer. CXCL12 expression in tumors was associated with ASC recruitment and localized to stromal cells expressing platelet-derived growth factor receptors Pdgfra and Pdgfrb. The role of this chemokine secreted by stromal cells in cancer progression was further investigated by using tissue-specific knockout models. SQ22536 inhibitor ASC deletion of CXCL12 gene in the Pdgfr + lineages suppressed tumor growth and EMT, indicating stroma as the key source of CXCL12. Clinical sample analysis revealed that CXCL12 expression by peritumoral adipose stroma is increased in obesity, and that the correlating increase in Pdgfr/CXCL12 expression in the tumor is linked with decreased survival of patients with prostate carcinoma. Our study establishes ASC as the source of CXCL12 driving tumor aggressiveness and outlines an approach to treatment of carcinoma progression.Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFβ expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (11) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit . The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.In spite of significant recent advances in our understanding of the genetics and cell biology of glioblastoma, to date, this has not led to improved treatments for this cancer. In addition to small molecule, antibody, and engineered virus approaches, engineered cells are also being explored as glioblastoma therapeutics. This includes CAR-T cells, CAR-NK cells, as well as engineered neural stem cells and mesenchymal stem cells. Here we review the state of this field, starting with clinical trial studies. These have established the feasibility and safety of engineered cell therapies for glioblastoma and show some evidence for activity. Next, we review the preclinical literature and compare the strengths and weaknesses of various starting cell types for engineered cell therapies. Finally, we discuss future directions for this nascent but promising modality for glioblastoma therapy.The incidence rate of cancer is steadily increasing all around the world, and there is an urgent need to develop novel and more effective treatment strategies. Recently, bacterial therapy has been investigated as a new approach to target cancer, and is becoming a serious option. Streptococcus strains are among the most common and well-studied virulent bacteria that cause a variety of human infections. Everyone has experienced a sore throat during their lifetime, or has been asymptomatically colonized by streptococci. The ability of Streptococcus bacteria to fight cancer was discovered more than 100 years ago, and over the years has undergone clinical trials, but the mechanism is not yet completely understood. Recently, several animal models and human clinical trials have been reported. Streptococcal strains can have an intrinsic anti-tumor activity, or can activate the host immune system to fight the tumor. Bacteria can selectively accumulate and proliferate in the hypoxic regions of solid tumors. Moreover, the bacteria can be genetically engineered to secrete toxins or enzymes that can specifically attack the tumors.

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