Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy

Evolution of Our Understanding of Myeloid Regulatory Cells: From MDSCs to Mregs

The term myeloid-derived suppressor cells (MDSCs) was first suggested in 2007 in order to reflect the origin and function of myeloid cells during immunosuppression in cancer and other pathologic conditions. Emerging evidence suggests that MDSCs suppress CTL and Th1 responses in malignant diseases while they regulate effective immune responses in parasitic and helminth infections as well as Th17 inflammatory response during autoimmune diseases. Based on these data, the term myeloid regulatory cells (Mregs) more accurately reflects their function and interactions with different cells of the immune system during diseased conditions. Here, we provide evidence on the multifaceted function of Mregs during diseased state

Novel Engineered Porous Materials for the Removal of Lead from Water

The estimated average blood lead level for the population younger than 5 years in the United States is approximately 100 times higher than ancient background levels, indicating that substantial sources of lead exposure exist in the environment. This research is focused on the removal of lead from water with a functionalized zeolite. Functionalization improves adsorption behavior to achieve adsorbent materials with high capacity and stability with potential multiple re-uses. The lead sorption from water onto an Australian zeolitic mineral (clinoptilolite) unmodified and modified with sulfide-based reagents is investigated with batch and fixed bed column experiments. The effect of solution pH, functional groups’ concentration, and competing ions are studied on the adsorption behavior. Functional groups stability and particles regeneration are also examined. The idea of functionalizing zeolite with sulfides for the removal of lead is able to develop a unique adsorbent material. The use of reactive sulfides attached to zeolite is a novel development. The functionalized zeolite was characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), scanning electron microscope (SEM) and energy disperse spectroscopy (EDS). The reactivity, sorption kinetics behavior, and retention isotherms for lead were determined to permit modeling and design of processes for optimum contaminant removal. The significance of this research work is realized by its ability to create an engineered mesoporous-macroporous medium for lead adsorption by incorporating the functionality into the natural zeolite; this is accomplished using sulfides-based reagents. Sulfide-based reagents are ideal candidates for heavy metal remediation applications because of their soft basic frameworks, which should show increased affinity toward softer Lewis acids. The functional design and data analysis are significant to the scientific community, and are fundamental for the water industry, as they provide the knowledge necessary for developing next-generation water filtration media using zeolite materials

Diplostomiasis in cultured rainbow trout (Oncorhynchus mykiss) in Iran

This is the first report of Diplopstomiasis among rainbow trout in Iran. In June 1997 Diplopstomiasis occurred within rainbow trout farm in west Azarbayjan province. Diagnosis was Diplostomum spathaceum. This farm has the sedimentation pound. 56 species fingerling with average body weight 4.4 gr examined. Maximum and minimum metacercaria counting revealed one to five pieces respectively. In autopsies of 7 cultured fishes with average body weight 29.2 gr maximum metacercaria counting was 25 and minimum was 1 metacercaria in each eye. 8 breeder with average body weight 572.8 gr examined and infestation was 100 percent. The Lymnaeidae snails near sedimentation pound autopsies and larval stage of parasite did not exist

Cancer immunotherapy: Re-programming cells of the innate and adaptive immune systems

Cancers utilize multiple mechanisms to overcome immune responses. Emerging evidence suggest that immunotherapy of cancer should focus on inducing and re-programming cells of the innate and adaptive immune systems rather than focusing solely on T cells. Recently, we have shown that such a multifaceted approach can improve immunotherapy of breast cancer

Role of Epigenetic Modification and Immunomodulation in a Murine Prostate Cancer Model

INTRODUCTION. Decreased expression of highly immunogenic cancer-testis antigens (CTA) might help tumor to achieve low immunogenicity, escape immune surveillance and grow unimpeded. Our aim was to evaluate CTA expression in tumor and normal tissues and to investigate possible means of improving the immune response in a murine prostate cancer (CaP) model by using the combination of epigenetic modifier 5-azacitidine (5-AzaC) and immunomodulator lenalidomide. No study to date has examined the effect of this combination on the prostate cancer or its impact on antigen-presenting cells (APC). MATERIALS AND METHODS. Gene microarrays were performed to compare expression of several CTA in murine prostate cancer (RM-1 cells) and normal prostate. RM-1 cells were treated with 5-AzaC and real-time PCR was performed to investigate the expression of several CTA. Western blotting was used to determine whether expression of CTA-specific mRNA induced by 5-AzaC resulted in increase in the corresponding protein. Effect of the epigenetic agents and immunomodulators was assessed on dendritic cells (DC) using flow cytometry, ELISA and T-cell proliferation assay. RESULTS. Gene arrays demonstrated decreased expression of 35 CTA in CaP tissue compared to normal prostate. 5-AzaC treatment of RM-1 prostate cancer cells upregulated the expression of all 13 CTA tested in a dose-dependent fashion. DC were treated with 5-AzaC and lenalidomide and the expression of surface markers MHC Class I, MHC Class II, CD80, CD86, CD 205, and CD40 was increased. Combination of 5-AzaC and lenalidomide enhances the ability of DC to stimulate T-cell proliferation in mixed leukocyte reaction. Secretion of IL-12 and IL-15 by DC increased significantly with addition of 5-AzaC or 5-AzaC and lenalidomide. CONCLUSIONS. Decreased expression of CTA by prostate cancer may be a means of escaping immune monitoring. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide increased tumor immunogenicity and enhanced DC function and may be used in the treatment of advanced prostate cancer

Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25+ NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25+ NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy

Immunotherapy of Cancer: Reprogramming Tumor-Immune Crosstalk

The advancement of cancer immunotherapy faces barriers which limit its efficacy. These include weak immunogenicity of the tumor, as well as immunosuppressive mechanisms which prevent effective antitumor immune responses. Recent studies suggest that aberrant expression of cancer testis antigens (CTAs) can generate robust antitumor immune responses, which implicates CTAs as potential targets for immunotherapy. However, the heterogeneity of tumor cells in the presence and quantity of CTA expression results in tumor escape from CTA-specific immune responses. Thus, the ability to modulate the tumor cell epigenome to homogenously induce expression of such antigens will likely render the tumor more immunogenic. Additionally, emerging studies suggest that suppression of antitumor immune responses may be overcome by reprogramming innate and adaptive immune cells. Therefore, this paper discusses recent studies which address barriers to successful cancer immunotherapy and proposes a strategy of modulation of tumor-immune cell crosstalk to improve responses in carcinoma patients

Tumor escape and progression under immune pressure.

Although cancers develop and progress in immunocompetent hosts, immunological therapies for cancer have been proposed as alternative or complementary approaches to more standard therapy. It was initially thought that tumors were silent to the immune system, and that breaking immunological tolerance could result in immune-mediated tumor rejection. However, we have learned that cancer patients have preexisting immune responses against their tumor antigens which, nevertheless, fail to protect them, in part because of increased activity of the immune suppressor cells such as myeloid-derived suppressor cells (MDSC). Attempts to develop combinatorial therapies by depleting suppressor cells or blocking suppressor pathways and at the same time actively inducing immune responses in vivo or adoptively transferring tumor-specific T cells have largely failed. Very limited success has been achieved only against melanoma, using adoptive T-cell therapy, or prostate cancer, using a vaccine which improves patient survival but has no apparent inhibitory effect on disease progression. Further progress in the immunotherapy of cancer has been halted because of a poor understanding of the cellular components of the immune responses working together in favor of or against the tumors, as well as our inability to reliably reprogram immune responses towards the most effective phenotypes against cancer. This special issue is focused on understanding the escape mechanisms that malignant cells develop to hijack antitumor immune responses as well as strategies to overcome tumor escape. Four main areas that are covered in this issue include the following. Opposing Functions of the Immune System in Tumor Inhibition and Tumor ProgressionRobert Schreiber proposed the term “cancer immunoediting” in order to broadly describe the dual host-protecting and tumor-sculpting actions of the immune system that not only survey for, and eliminate, nascent malignant cells but also shape neoplastic disease through equilibrium and escape mechanisms. In this issue, M. Aris et al. discuss the dual function of the immune system in controlling and promoting tumor progression in cutaneous melanoma. They propose that tumor evolution is because of a continuous feedback between tumor cells and their environment, and thus different combinatorial therapeutic approaches can be implemented according to the tumor stage. A. Amedei et al. discuss recent knowledge on the contribution of T cells in oncogenesis. They review the different types, “friend or foe,” of T-cell response in gastric cancer. Tumor-Associated Modulation of Immune Checkpoint MoleculesUpon activation, T cells develop negative feedback regulatory mechanisms in order to avoid overstimulation. These include the expression of checkpoint molecules such as PD-1 and CTLA-4. T cells that recognize and respond to tumor antigens produce IFN-γ. A dual function of IFN-γ is the induction of apoptosis in target cells and upregulation of PD-L1 that interacts with PD-1 positive T cells, thereby resulting in the exhaustion of tumor-reactive T cells. Expression of CTLA-4 on activated T cells also results in T-cell anergy upon interaction with costimulatory molecules on DCs. S. Sapozink et al. describe new immunomodulatory approaches currently in the development pipeline, with focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described lymphocyte inhibitory targets, CTLA4 and PD-1. E. Rozali et al. provide an extensive review of the literature on the immunoregulatory role of PD-L2 in cancer-induced immune suppression and discuss the results of recent studies targeting PD-L2 in cancer. L. Cruz-Merino et al. discuss immune escape mechanisms in Hodgkin’s lymphoma (HL) and summarize the clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on treatment strategies. L. Farnault et al. introduce various mechanisms involved in the escape of hematological malignancies from NK-cell surveillance. These include NK-cell qualitative and qualitative deficiencies that occur through modulating the inhibitory and activating stimuli. Tumor-Induced Immune SuppressionMalignant cells produce cytokines and chemokines that facilitate the expansion or differentiation of immune suppressor cells such as Tregs, MDSC, and M2 macrophages. G. Zhou and H. Levitsky summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction. A particularly interesting notion that is touched upon involves tumor-independent treatment-induced homeostatic counter-regulation. M. Jadus et al. cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. They also review the history of immunotherapy directed towards lung cancers. N. Hao et al. discuss the role of tumor-associated macrophages including M1 and M2 subsets during tumour progression and metastasis, highlighting the immunosuppressive role of M2 macrophages. V. Levina et al. investigate the role of indoleamine 2,3-dioxygenase (IDO1) in tumor escape and metastasis using 4T1 mammary carcinoma model. They show that IDO1 can not only suppress antitumour immune responses but also promote tumour cell proliferation. Improved Immunotherapeutic Strategies to Overcome Tumor EscapeImmunotherapy combined with blockade of immune suppressor pathways has been developed to overcome tumor-induced immune suppression. Cornelissen et al. discuss the interplay between a dual function of the immune responses against mesothelioma which can either inhibit or stimulate tumor growth and review the challenges associated with immunotherapy. They also discuss possible strategies and opportunities to overcome tumor escape. R. Casalegno-Garduño et al. analyze the expression of the leukemia-associated antigen receptor for hyaluronan acid-mediated motility (RHAMM) in patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Their results suggest that immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the clinical outcome in AML/MDS patients. S.Wallner et al. summarize the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy. H. Nagai et al. demonstrate that sorafenib-induced Th1 dominance can prevent the escape of tumor cells from the host immune system in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC).Overall, this special issue provides a well-rounded synopsis of representative research efforts addressing the issues related to “tumor escape and progression under immune pressure.