In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.

Minority U.S. populations are underrepresented in cancer clinical trials. This review appraises the impact of the disparity in clinical trial participation by minority patients in the current era of cancer immunotherapy. Enrollment on pivotal trials leading to U.S. regulatory approval of immune checkpoint inhibitors showed poor representation of minority ethnic groups. Specifically, we found that black patients constitute less than 4% of all patients enrolled across multiple trials that supported the approval of immune checkpoint inhibitors for the treatment of lung cancer. Similar underrepresentation was observed for trials conducted in renal cell carcinoma and other tumor types. Since efficacy of immunotherapy is only observed in a subset of patients, the use of predictive biomarkers to identify responders along with new strategies to expand the benefit to a larger subset of patients are current areas of active investigation. The inadequate representation of minority patients on immunotherapy clinical trials could perpetuate outcome disparity because the unique biology of the host and the tumors from this subpopulation is not accounted for as new treatment algorithms to guide optimal use of immunotherapy are developed for use in the real world.

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Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.

SummaryInflammatory bowel disease (IBD), a chronic intestinal inflammatory condition that affects millions of people worldwide, results in high morbidity and exorbitant health-care costs. The critical features of both innate and adaptive immunity are to control inflammation and dysfunction in this equilibrium is believed to be the reason for the development of IBD. miR-155, a microRNA, is up-regulated in various inflammatory disease states, including IBD, and is a positive regulator of T-cell responses.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c) and decreased macrophages (F4/80) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4 T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4 T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD. NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.

Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signaling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer.

The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3 + Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-b1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-b1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-b1-induced-Treg generation from Smad3 À/À mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-jB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-b1 significantly attenuates NF-jB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-jB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-jB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-b1-induced-Treg cells for therapeutic purposes. There are reports documenting a reduction in the number or function of Treg cells in patients with numerous autoimmune diseases, including diabetes, rheumatoid arthritis, psoriasis, myasthenia gravis or sarcoidosis [12][13][14][15]. Thus, one possible way for restoration of self-tolerance in these patients could be by the infusion of Treg cells having an increased ability to control ongoing autoimmune destruction. Due to the limited availability of nTreg cells, in vitro generated iTreg cells may serve as an alternative source of Treg cells for therapeutic purposes. There is strong evidence that these Foxp3 + iTreg cells can prevent/delay the development of Type 1 Diabetes in the NOD mice [16,17]. Hence, the regulation of Foxp3 expression during iTreg generation is of considerable interest. Relatively little is known about the regulation of Foxp3 in the periphery. The essential roles of IL-2, TGF-b and TCR signaling in iTreg generation have been established [11,[18][19][20]. However, it is unclear which particular arms in each of these pathways are important in FoxP3 regulation. TGF-b1 is a pluripotent cytokine that has pronounced effects on T-cell-mediated immune suppression as well as on the control of autoimmunity. The binding of TGF-b1 to its receptor complex activates the intracellular kinase domain of TGF-bRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non-Smad proteins (Smad-independent pathway) [21]. After forming a heterodimer with phosphorylated Smad4, activated Smad2 and Smad3 translocate to the nucleus where they regulate TGF-b1-dependent gene expression. The generation of nTreg cells from the thymus of TGF...