Immune effector and regulatory cells in the tumor microenvironment are key factors in tumor development and progression as the pathogenesis of cancer vitally depends on the multifaceted interactions between various microenvironmental stimuli provided by tumor-associated immune cells. Immune regulatory cells participate in all stages of cancer development from the induction of genomic instability to the maintenance of intratumoral angiogenesis, proliferation and spreading of malignant cells, and formation of premetastatic niches in distal tissues. Dendritic cells in the tumor microenvironment serve as a double-edged sword and, in addition to initiating potent anti-tumor immune responses, may mediate genomic damage, support neovascularization, block anti-tumor immunity and stimulate cancerous cell growth and spreading. Regulatory dendritic cells in cancer may directly and indirectly maintain antigen-specific and non-specific T cell unresponsiveness by controlling T cell polarization, MDSC and Treg differentiation and activity, and affecting specific microenvironmental conditions in premalignant niches. Understanding the mechanisms involved in regulatory dendritic cell polarization and operation and revealing pharmacological means for harnessing these pathways will provide additional opportunities for modifying the tumor microenvironment and improving the efficacy of different therapeutic approaches to cancer.

Irritable bowel syndrome and interstitial cystitis frequently overlap. We have shown that acute colitis sensitizes urinary bladder afferents to both mechanical and chemical stimuli and that chronic colitis similarly produces neurogenic cystitis. We hypothesize that chronic irritation of the colon releases neuropeptides from bladder afferents, leading to receptor sensitization and neurogenic inflammation. Female Sprague-Dawley rats received intrarectal trinitrobenzenesulfonic acid (TNBS) or vehicle 3 days following either systemic capsaicin (CP) pretreatment or vehicle. Ten days later, action potentials of single-unit pelvic C-fiber afferents with receptive fields in the bladder were recorded under urethane anesthesia during graded bladder distensions (UBD) or intravesical capsaicin (vCP) administration. In controls, UBD increased bladder afferent firing in proportion to intravesical pressure. At intravesical pressures of 30 mmHg and above, the percent increase in afferent firing was significantly accentuated following TNBS compared with controls (1,222 +/- 176 vs. 624 +/- 54%, P< 0.01). The response to vCP was also enhanced (4,126 +/- 775 vs. 1,979 +/- 438%, P < 0.01). Systemic depletion of neuropeptides from sensory nerves abolished these effects. Histological examination of the bladders revealed an increase in mast cell density in TNBS-treated animals compared with controls (18.02 +/- 1.25 vs. 3.11 +/- 0.27 mast cells/x100 field, P < 0.01). This effect was significantly ameliorated with CP (10.25 +/- 0.95, P < 0.5 vs. TNBS-treated animals). In summary, chronic colonic irritation in the rat sensitizes urinary bladder afferents to noxious stimuli and causes mast cell infiltration in the bladder. Depletion of neuropeptides from sensory afferents diminishes these effects, suggesting they play an important role.

BackgroundCellulose-based materials have been used for centuries to manufacture different goods derived from forestry and agricultural sources. In the growing field of nanocellulose applications, its uniquely engineered properties are instrumental for inventive products coming to competitive markets. Due to their high aspect ratio and stiffness, it is speculated that cellulose nanocrystals (CNC) may cause similar pulmonary toxicity as carbon nanotubes and asbestos, thus posing a potential negative impact on public health and the environment.MethodsThe present study was undertaken to investigate the pulmonary outcomes induced by repeated exposure to respirable CNC. C57BL/6 female and male mice were exposed by pharyngeal aspiration to CNC (40 μg/mouse) 2 times a week for 3 weeks. Several biochemical endpoints and pathophysiological outcomes along with gene expression changes were evaluated and compared in the lungs of male and female mice.ResultsExposure to respirable CNC caused pulmonary inflammation and damage, induced oxidative stress, elevated TGF-β and collagen levels in lung, and impaired pulmonary functions. Notably, these effects were markedly more pronounced in females compared to male mice. Moreover, sex differences in responses to pulmonary exposure to CNC were also detected at the level of global mRNA expression as well as in inflammatory cytokine/chemokine activity.ConclusionsOverall, our results indicate that there are considerable differences in responses to respirable CNC based on gender with a higher pulmonary toxicity observed in female mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0140-x) contains supplementary material, which is available to authorized users.

Since 1948, when Farber et al. introduced aminopterin, the first chemotherapeutic agent, more than 100 such agents have come into use. Initially, antitumor chemotherapies were thought to produce only antiproliferative or cytotoxic effects on dividing tumor cells as it was often associated with the damage to healthy tissues and the development of resistant tumor clones. However, that view has been changing as a consequence of recent demonstrations that several antineoplastic drugs, even at low doses, have antiangiogenic and sometimes immunomodulating effects. In addition, new studies indicate that lowering the dose of conventional cytotoxic agents and combining chemotherapy with other modalities may not only decrease the toxicity of conventional chemotherapy, but also up-regulate the efficacy of different anticancer therapies. Giving chemotherapy in this manner has several potential advantages, including impediment of the onset of mutation-dependent mechanisms of acquired drug resistance and increase in the efficacy and durability of combinatorial therapeutic modalities. Certain "immunogenic" forms of cancer chemotherapy may cause indirect activation of immune cells due to the accessibility of tumor antigens and certain "danger" signals. Furthermore, new findings indicate that several chemotherapeutic agents can directly activate immune cells when used in ultra low noncytotoxic concentrations, the new phenomenon that was termed chemoimmunomodulation. The goal of this review is to analyze the immune modulating properties of antineoplastic chemotherapeutic agents and present new evidence of the immunostimulating potentials of several agents used in low and ultra low nontoxic doses. Therapeutic potentials of combined chemo-immunotherapeutic regimens have been extensively reviewed in a variety of recent publications and will not be discussed.

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