Immune Surveillance Mechanisms Research Articles

Human Immunodeficiency Virus (HIV) Status Drives Diffuse Large B Cell Lymphoma through Oncogenic Signaling Pathways

Introduction:Diffuse Large B cell Lymphoma (DLBCL) is up to 80-fold more likely to occur and follows a more aggressive clinical course in HIV positive (+) individuals compared to HIV negative (-) individuals. Moreover, the vast majority frequently present at advanced stages with high tumor burdens with poor prognosis. The molecular pathology underpinning the clinical features of DLBCL in HIV(+) patients relative to the general population is poorly understood; however, it is suspected to depend on decreased host immune surveillance and alternative mechanisms of tumorogenesis. In this study, we sought to identify the differences in gene expression between HIV(+) and HIV(-) DLBCL cohorts that may contribute to the unique features of HIV(+) DLBCL.Methods:We performed a retrospective gene expression profiling (GEP) study using a total of 70 DLBCL cases, 31 HIV(+) obtained from AIDS Cancer Specimen Resource Network (https://acsr.ucsf.edu/) and 39 HIV(-) institutional cases. The H&Es for all cases were reviewed by a hematopathologist and tumor content determined. Cases that did not meet the minimum tumor content threshold of 70% were macro-dissected. RNA was extracted from 4x 5µm formalin fixed, paraffin embedded (FFPE) sections using the Qiagen AllPrep DNA/RNA FFPE Kit and quantified using a NanoDrop. The Lymph2Cx assay, which accurately subtypes DLBCL in FFPE tissues (Scott et al 2014), was used to determine the cell of origin (COO) subtypes: Germinal Center B cell (GCB), Activated B cell (ABC) and Unclassifiable (UNC). Digital GEP was performed using the NanoString PanCancer Pathways and Immunology panels, targeting a total of over 1300 genes with known roles in cancer or immune signaling.Results:Of the 31 HIV(+) cases, Lymph2Cx subtyping showed 74% (23/31) were GCB, 13% (4/31) were ABC and 13% (4/31) were UNC. In a similar distribution to the HIV(+), and comparable to prior literature, 54% (21/39) of HIV(-) cases were GCB, 31% (12/39) were ABC and 15% (6/39) were UNC. Differential gene expression was observed between HIV(+) and HIV(-) cases, but no association with COO subtype was found. When the data was re-analyzed within the GCB subtype alone, stratification by HIV status was observed. Particularly, reduced expression of genes associated with immune regulation was observed in HIV(+) GCB cases compared to HIV(-) GCB cases. In contrast, expression of genes associated with cell cycle regulation and homologous recombination (the predominate double stranded DNA repair pathway employed during the cell cycle), were higher in HIV(+) cases compared to HIV(-) GCB cases.Conclusions:The results show, that within the GCB subtype, marked differences in gene expression are associated with HIV status. Our results suggest that the aggressive nature of DLBCL in HIV(+) patients may, in part, be mediated by enhanced cell proliferation potentiated by aberrant DNA repair. DisclosuresFogel:Natural Selection Inc: Employment. Liu:Natural Selection Inc: Employment. Lamers:Bioinfoexperts LLC: Employment.

Immunonutrition before esophagectomy: Impact on immune surveillance mechanisms

Preoperative oral immunonutrition was demonstrated to improve immune response and to decrease the infection rate in patients with cancer. This study aimed to assess how immunonutrition could influence the immune cell response in the mucosal microenvironment of esophageal adenocarcinoma. Therefore, A prospective cohort of consecutive patients undergoing esophagectomy for esophageal adenocarcinoma was enrolled. A subgroup of them was given preoperative oral immunonutrition with Oral Impact® and was compared to those who received no preoperative supplementation. Mucosal samples from healthy esophagus were obtained at esophagectomy. Histology, immunohistochemistry, gene expression analysis, and cytofluorimetry were performed. Markers of activation of antigen-presenting cells (CD80, CD86, and HLA-I), innate immunity (TLR4 and MyD88), and cytotoxic lymphocyte infiltration and activation (CD8, CD38, CD69, and CD107) were measured. In all, 50 patients received preoperative Oral Impact® and 129 patients received no nutritional support. CD80, CD86, MyD88, and CD69 messenger RNA expression was significantly increased in patients receiving immunonutrition compared to controls. In the subgroup of patients with stages I-II cancer, the rate of epithelial cells expressing CD80 and HLA-ABC was significantly higher in those receiving immunonutrition compared to controls as well as CD8+ CD28+ cell rate. Immunonutrition administration before surgery was significantly associated to increased degranulating CD8 and natural killer cells (CD107+) infiltrating the healthy esophageal mucosa. All the comparisons were adjusted for cancer stage and preoperative therapy. In conclusion, in healthy esophageal mucosa of patients undergoing esophagectomy, a 5-day course of immunonutrition enhances expression of antigen-presenting cells activity and increased CD8+ T cell activation and degranulating activity. Further studies are warranted to understand the clinical implication in terms of cancer recurrence.

Correlation Between Neutrofil-Limphocyte Ratio Before Chemoteraphy and Objective Response Platinum based Chemoteraphy on Lung Cancer Patient

Background: Lung cancer is the leading cause of death from cancer. One type of cancer is non-small cell lung cancer (NSCLC). The body fights against cancer cells by immune surveillance mechanisms involving the role of neutrophils and lymphocytes. Chemotherapy is a modality that is usually used as a therapy in patients’ NSCLC. To assess chemotherapy’s prognostic, research needs to be done to find the relationship between the neutrophil-lymphocytes ratio before chemotherapy with objective response after chemotherapy in patients with NSCLC
 Methods: This study was an observational study of retrospective cohort analytics which samples are secondary data from medical records of NSCLC patients in RSUD Dr. Soetomo who received chemotherapy by linking the neutrophils-lymphocytes ratio before chemotherapy with objective response after chemotherapy based on RECIST’s criteria and analyzed by spearman correlation test method and RNL cut off value with ROC curve and kappa test
 Results: Sixty-four subjects were analyzed in this study, the relationship of neutrophil-lymphocyte ratio with chemotherapy objective response after 2 cycles with P=0.354 (

CGAS surveillance of micronuclei links genome instability to innate immunity.

SummaryDNA is strictly compartmentalised within the nucleus to prevent autoimmunity1; despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage2–6. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localises to micronuclei arising from genome instability in a model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. These micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by their own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis7, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS binds to and is activated by chromatin and, consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA-damage are cell-cycle dependent. Furthermore, by combining live-cell laser microdissection with single cell transcriptomics, we establish that induction of interferon stimulated gene expression occurs in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, cGAS recognition of micronuclei may act as a cell-intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes.

Abstract LB-181: Cutaneous SCC may escape immune surveillance by secreting complement factor H

Abstract Developing tumors evade elimination by the immune system using a variety of mechanisms. Evidence suggests that cutaneous squamous cell carcinomas (cSCCs) may evade immune system surveillance by secreting complement factor H (CFH), a regulatory protein of the complement system. As part of its normal function, CFH binds to glycosaminoglycans on the surface of host cells where it acts as a cofactor for Factor I mediated C3b cleavage and accelerates the decay of the C3-convertase C3bBb. This mechanism for protecting self-cells also involves shifting the immune response from a pro-inflammatory T-helper-1 cell to an anti-inflammatory regulatory T-cell response. Data presented here suggest that some cSCCs have the ability to upregulate expression of CFH and studies have shown that this could be in response to the pro-inflammatory cytokine interferon-γ. We suggest that, in our cSCC samples, a potential negative-feedback loop exists in which the initial immune response to the developing tumor triggers expression of an immunosuppressive molecule, allowing the cancer to create an environment conducive to evading immune surveillance mechanisms. Note: This abstract was not presented at the meeting. Citation Format: Ellise Loomis, Christopher Pulford, Chandana Uppalapati, Agnes Pascual, McKale Montgomery, Kathryn J. Leyva, Elizabeth E. Hull. Cutaneous SCC may escape immune surveillance by secreting complement factor H [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2017-LB-181

MiR-2909 regulates ISGylation system via STAT1 signalling through negative regulation of SOCS3 in prostate cancer.

One of the well-document strategies adopted by tumour cells for progression is to evade immune surveillance mechanisms. An understanding of the tight interaction between immunity and progression of cancer can provide novel treatment options for different malignancies including prostate cancer (PCa). Here, we have shown that AATF genome encoded miR-2909, known to play role both in immunity and cancer upregulates various interferon stimulating genes (ISGs) including ISGylation system through STAT1. Our results revealed that miR-2909 up-regulates STAT1 through negative regulation of SOCS3 and not through up-regulation of Type 1 interferon (IFN) production. It was observed that inhibition of ISGylation reduced the proliferation potential of PCa cells. Furthermore, androgens were found to negatively regulate ISGylation in LNCaP cells through androgen receptor signalling independently of miR-2909. TGF-β mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression. Collectively, these studies suggest that miR-2909 could play a vital role in prostate carcinogenesis through modulation of ISGylation system and TGFβ signalling via STAT1.

Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer.

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 2779-83. ©2017 AACR.

Immune surveillance in melanoma: From immune attack to melanoma escape and even counterattack

ABSTRACTPharmacologic inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death receptor-1 (PD1) has resulted in unprecedented durable responses in metastatic melanoma. However, resistance to immunotherapy remains a major challenge. Effective immune surveillance against melanoma requires 4 essential steps: activation of the T lymphocytes, homing of the activated T lymphocytes to the melanoma microenvironment, identification and episode of melanoma cells by activated T lymphocytes, and the sensitivity of melanoma cells to apoptosis. At each of these steps, there are multiple factors that may interfere with the immune surveillance machinery, thus allowing melanoma cells to escape immune attack and develop resistance to immunotherapy. We provide a comprehensive review of the complex immune surveillance mechanisms at play in melanoma, and a detailed discussion of how these mechanisms may allow for the development of intrinsic or acquired resistance to immunotherapeutic modalities, and potential avenues for overcoming this resistance.

Cancer Immunoprevention and Public Health.

The power of cancer immune surveillance has been documented beyond doubt, and the successful exploitation of immune response to cancer has started a new era in the war against cancer. Cancer biologists have recognized immunoevasion as an emerging hallmark in addition to the six hallmarks of cancer. Besides the natural connection between the immune system and cancer development, most established environmental risk factors are now known to interfere with immune surveillance mechanisms. Genetic variations regulating immunity may also modulate cancer susceptibility, but evidence for this is currently limited. Molecular cross talk linking “immune” and “genomic” surveillance pathways has been characterized. It appears that immune mechanisms may contribute to the effects of common cancer risk factors. We provide an updated overview of evidence for cancer immune surveillance, cancer risk factors interfering with it, and interventions to enhance cancer immune surveillance as tools to complement ongoing vaccine development efforts for cancer immunoprevention. Although there is a lot of support for cancer immunoprevention with simple lifestyle modifications from observational studies, there is an urgent need for clinical trials to establish the effectiveness of this approach for public health benefits.

Topical chemo-immunotherapy converts a pro-tumorigenic tumor microenvironment to a pro-inflammatory phenotype in human cutaneous squamous cell carcinoma

Abstract We have previously demonstrated that microneedle array (MNA) delivery of anti-tumor agents improves survival in mouse models of melanoma and non-melanoma skin cancers and induces cell death in freshly excised human cutaneous squamous cell carcinomas (cSCCs). As tumors employ strong immunosuppressive and tumor-promoting mechanisms that prevent their elimination by immune surveillance mechanisms and support their proliferation, we sought to determine if application of MNAs containing anti-tumor agents could abrogate their protumorigenic phenotype and promote an anti-tumor phenotype in a human model of cSCC, the second most common human malignancy worldwide. To accomplish this, we compared Nanostring gene expression data from human cSCCs treated with MNAs containing doxorubicin (MNA-Dox) to matched, untreated cSCC controls and unmatched normal skin. As compared to matched, untreated cSCC controls, MNA-Dox-treated cSCCs demonstrated significantly decreased expression of genes associated with a pro-tumorigenic environment, including IDO, ARG2, S100A7 and VEGF-A. Further, MNA-Dox-treated cSCCs demonstrated significantly increased expression of genes associated with an anti-tumor phenotype, including CXCL14, HMGB1, P53, and Caspase-8. Comparison of MNA-Dox-treated cSCCs and unmatched, untreated normal skin suggested a reversion of a pro-tumorigenic phenotype to a normal skin phenotype, with similarly low expression of pro-tumorigenic genes seen in both groups. Together, these results suggest the potential of MNA-administered doxorubicin to effectively transform a pro-tumor microenvironment to one favoring the induction of tumor immunity in a human cSCC.

CD56bright NK IL-7Rα expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections.

Several lines of evidence support the concept that NK cells play an important role in control of hepatitis C virus (HCV) infection via cytokine secretion and cytotoxicity. IL-7 is a homeostatic cytokine with a role in T cell development, activation, proliferation, and cytokine secretion. The IL-7Rα chain [cluster of differentiation (CD)127] is expressed on NK cells, with greatest abundance on the CD56brightCD16dim/- (CD56bright) subset. Here, we measured CD127 expression on CD56bright, CD56dimCD16+ (CD56dim), or CD56negCD16+ (CD56neg) NK cell subsets of 25 uninfected donors (UD); 34 chronic HCV-infected, treatment-naïve; 25 HIV-infected, virally suppressed on antiretroviral therapy (ART); and 42 HCV-HIV-coinfected subjects on ART. Interestingly, CD127 expression on CD56bright NK cells negatively correlated with HCV plasma levels in HCV monoinfection and HCV-HIV coinfection. IL-7 induced CD69 expression, as well as IFN-γ production, in CD56bright NK cells and also enhanced the IFN-α-induced CD69 expression on these cells. The latter was impaired in HIV infection. Furthermore, IL-7 induced B cell lymphoma 2 (BCL-2) expression and cell cycling of CD56bright NK cells, and this effect was impaired in HCV- and HIV-infected subjects. Whereas IL-7-stimulated CD56bright NK cell degranulation appeared intact in all cohorts, we observed impaired IL-7-activated NK cell cytolytic function in HCV- and HIV-infected subjects. Finally, IL-7-induced phosphorylation of STAT-5 (pSTAT-5) signaling was impaired in NK cells of subjects with chronic viral infection, and this was reversible upon 6 mo of viral suppression with IFN-free HCV therapy. These results implicate that IL-7-dependent NK cell activation and effector function may be other host immune surveillance mechanisms that are impaired in viral infections.

Myeloid-derived suppressor cells and T regulatory cells in tumors: unraveling the dark side of the force.

Important conceptual advances in tumor immunology over the last years have shifted the paradigm from focusing on the malignant cell to the importance of host immune components in the design of successful immunotherapies. The immune system, through sophisticated innate and adaptive immune surveillance mechanisms, inhibits the growth and establishment of tumors. However, despite immune surveillance, tumors still escape and grow, mainly as a result of endowed tumor-induced immunosuppressive circuits. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are the major components of these regulatory networks that facilitate tumor immune escape and significantly compromise the efficacy of current immunotherapies. A better understanding of the induction, function, and expansion of these powerful regulatory compartments represents a major challenge on the clinical benefit of current treatments and may foster the design of novel cancer immunotherapies.

Human T-Cell Leukemia Virus Type 1 Infection and Adult T-Cell Leukemia.

Human T-cell leukemia virus type 1 (HTLV-1) is the first retrovirus discovered to cause adult T-cell leukemia (ATL), a highly aggressive blood cancer. HTLV-1 research in the past 35years has been most revealing in the mechanisms of viral oncogenesis. HTLV-1 establishes a lifelong persistent infection in CD4+ T lymphocytes. The infection outcome is governed by host immunity. ATL develops in 2-5% of infected individuals 30-50years after initial exposure. HTLV-1 encodes two oncoproteins Tax and HBZ, which are required for initiation of cellular transformation and maintenance of cell proliferation, respectively. HTLV-1 oncogenesis is driven by a clonal selection and expansion process during which both host and viral factors cooperate to impair genome stability, immune surveillance, and other mechanisms of tumor suppression. A better understanding of HTLV-1 biology and leukemogenesis will reveal new strategies and modalities for ATL prevention and treatment.

Expression Pattern of Immunosurveillance-Related Antigen Is a Critical Prognostic Factor of Adult T-Cell Leukemia/Lymphoma

Introduction: Human T-cell lymphotropic virus (HTLV-1) carriers are often found in coastal areas of the Kyushu-Okinawa region in Japan. Of the patients infected with the virus, only 2-5% will develop adult T-cell leukemia/lymphoma (ATLL). ATLL is classified into four clinical subtypes as follows: acute, lymphoma, chronic, and smoldering. Chronic-type ATLL has a better prognosis compared with acute and lymphoma types. However, in half of patients, chronic-type ATLL progresses to leukemia/lymphoma crisis. Abnormal expressions of CD58 and beta-2 microglobulin (b2M) were recently reported to be involved in the immune escape mechanism of tumor cells in diffuse large B-cell lymphoma (Pasqualucci et. al. Cancer Cell 2014). In our previous study, acute-type ATLL had significantly higher rates of CD58 gene deletion, which was associated with leukemia/lymphoma crisis in chronic-type ATLL (Yoshida et. al. Cancer Res 2014). However, the clinicopathological significance of HLA expression in ATLL patients remains controversial. In addition, we previously reported that the expression of programmed cell death ligand 1 (PD-L1), one of the regulatory factors of tumor immune responses, influenced disease prognosis in ATLL patients. Especially PD-L1 expression in stromal cells in tumor microenvironments is associated with better prognosis of ATLL (Miyoshi et al. Blood 2016). The present study evaluated the clinical relevance of HLA, b2M, and PD-L1 expressions, with particular emphasis on predicting overall survival of ATLL patients.Methods: We report the clinicopathological profiles of 123 patients diagnosed as having ATLL at Kurume University (Kurume, Japan) according to the 2008 World Health Organization classification system. Among these patients, 45 had the acute type and 52 had the lymphoma type, with a median age of 66 years (range, 13-90 years). We examined the immunohistological expressions of HLA and b2M proteins in all the 123 patients by using tissue microarray. The expression patterns and clinicopathological features were also examined statistically. All data were analyzed by using the STATA software version 12.0 (StataCorp, College Station, Texas).Results: In the immunohistochemical study, 91 (74%) of the 123 patients were positive for HLA, including 60 who were cell membrane positive (HLAm+), 31 who demonstrated cytoplasmic localization (HLAcy+), and 32 who were negative for HLA (HLA−). In addition, 89 (72%) of the 123 patients were positive for b2M, including 54 who were cell membrane positive (b2Mm+), 35 who demonstrated cytoplasmic localization (b2Mcy+), and 34 who were b2M negative (b2M−). The HLAm+b2Mm+ group, which showed membrane staining for both HLA and b2M, accounted for 48 cases (39%) in the present study (Table 1). In terms of clinical features, no significant differences were found between the HLAm+b2Mm+ group and the other groups. Immunophenotypical evaluation revealed significantly higher rates of CD30-positive lymphoma cells (P = 0.004) and PD-L1-positive stromal cells in microenvironments (PD-L1+stromal cells ≥50/HPF: miPD-L1high) in the HLAm+b2Mm+ patients (P = 0.008) than in the patients in other groups. Disease-specific survival (DSS) curves showed that the HLAm+b2Mm+ group had significantly better prognosis than the other groups (Figure 1-a). Especially the HLAm+b2Mm+ group with miPD-L1high had an excellent prognosis, with a 5-year survival rate of 77% (Figure 1-b). The multivariate analysis demonstrated that the membrane expressions of both HLA and b2M in lymphoma cells with increased number of PD-L1-positive stromal cells were an independent factor of good prognosis in ATLL (Table2).Conclusions: The results of our study demonstrated the following three points: 1) The expression patterns of HLA and b2M in the patients with ATLL varied. 2) The HLAm+b2Mm+ group showed significantly better prognosis than the other groups. Especially the HLAm+b2Mm+ group with miPD-L1high demonstrated the most favorable prognosis. These results suggest that the host immune surveillance mechanism for lymphoma cells in the HLAm+b2Mm+ group with mPD-L1high is still functioning. 3) The membrane expressions of HLA and b2M in ATLL cells are useful as a predictive marker of good prognosis and increase in the number of PD-L1-positive stromal cells in tumor microenvironments. [Display omitted] [Display omitted] [Display omitted] DisclosuresAsano:Chugai: Honoraria; Jannsen: Honoraria. Ohshima:Chugai: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau.

Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape.

Metastatic spread of tumour cells is the main cause of cancer-related deaths. Understanding the mechanisms of tumour-cell dissemination has, therefore, become an important focus for cancer research. In patients with cancer, disseminated cancer cells are often detectable in the peripheral blood as circulating tumour cells (CTCs) and in the bone marrow or lymph nodes as disseminated tumour cells (DTCs). The identification and characterization of CTCs and DTCs has yielded important insights into the mechanisms of metastasis, resulting in a better understanding of the molecular alterations and profiles underlying drug resistance. Given the expanding role of immunotherapies in the treatment of cancer, interactions between tumour cells and immune cells are the subject of intense research. Theoretically, cancer cells that exit the primary tumour site - leaving the protection of the typically immunosuppressive tumour microenvironment - will be more vulnerable to attack by immune effector cells; thus, the survival of tumour cells after dissemination might be the 'Achilles' heel' of metastatic progression. In this Review, we discuss findings relating to the interactions of CTCs and DTCs with the immune system, in the context of cancer immuno-editing, evasion from immune surveillance, and formation of metastases.

MASKING ANTI-PHAGOCYTIC SIGNAL OF TUMOR BY PRO-PHAGOCYTIC SIGNAL-A KEY TO IMMUREMENT OF CANCER CELL

<p>Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don’t eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro–phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.</p>

Immunological Consequences of Epithelial-Mesenchymal Transition in Tumor Progression.

Microenvironments that tumor cells encounter are different during the stages of cancer progression-primary tumor, metastasis, and at the metastatic site. This suggests potential differences in immune surveillance of primary tumor and metastasis. Epithelial-mesenchymal transition (EMT) is a key reversible process in which cancer cells transition into highly motile and invasive cells for dissemination. Only a tiny proportion successfully metastasize, supporting the notion of metastasis-specific immune surveillance. EMT involves extensive molecular reprogramming of cells conferring many clinically relevant features to cancer cells and affects tumor cell interactions within the tumor microenvironment. We review the impact of tumor immune infiltrates on tumor cell EMT and the consequences of EMT in shaping the immune microenvironment of tumors. The usefulness of EMT as a model to investigate metastasis-specific immune surveillance mechanisms are also explored. Finally, we discuss potential implications of EMT for tumor immunogenicity, as well as current immunotherapies and future strategies.

Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model

Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund’s adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1β,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p<0.001) decreases the inflammation in RA animal model. In conclusion, developed NLCs-based gel formulation loaded with MTX opens new avenues for developing novel therapeutic modality for RA patients with the acceptably minimum adverse effects.

CD80 down-regulation is associated to aberrant DNA methylation in non-inflammatory colon carcinogenesis.

BackgroundThe lack of positive costimulatory molecules represents one of the mechanisms by which tumor cells evade immune surveillance. Promoter hypermethylation plays a major role in cancer development through transcriptional silencing of critical genes. The aim of this study was to examine the expression of the costimulatory molecule CD80 in relationship with genomic methylation in non-inflammatory colon carcinogenesis.MethodsColonic mucosal samples were collected from healthy subjects (n = 30) and from dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, −3a, −3b and CD80 mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CD80 expression was assessed in HT29, HCT-15 and LoVo cell lines after treatment with the DNA-methyltransferase inhibitor 5-Aza-2′-deoxycytidine.ResultsCD80 mRNA levels were significantly lower in the non-inflammatory dysplastic colonic mucosa of patients with one or more methylated genes and inversely correlated with patients’ methylation scores (τ = −0.41, p = 0.05 and τ = −0.37, p = 0.05, respectively). Treatment with 5-Aza-2′-deoxycytidine significantly increased CD80 expression both in terms of the level of CD80 mRNA (p = 0.007) and of CD80+ cells (p = 0.003).ConclusionsThese results indicate that the failure of immune surveillance mechanisms in non-inflammatory colon carcinogenesis may be linked to genomic methylation directly or indirectly affecting CD80 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2405-z) contains supplementary material, which is available to authorized users.

Cancer as secondary immunodeficiency. Review

Secondary immunodeficiencys, previously presented in immunocompetent individuals. The lack of primary or secondary response to the presence of a foreign antigen, in the case of infections is a sentinel data in the diagnosis of immunodeficiency (can be primary or secondary), in the case of a self antigen may generate the presence of Cancer. Cancer has shown an increase in the prevalence and incidence globally. Most current medical treatments in cancer are focused primarily on immunomodulatory actions (immunosuppression / immune stimulation or both). Knowledge of key concepts from the perspective of innate and acquired immunity lead to cancer development, engaging immune surveillance and escape mechanisms of this that contribute to better understand the origin, behavior and treatment of neoplasm's. These treatments can cause immunological disorders such as allergy, anaphylaxis, lack of response immunogenicity care fields specialist in allergy and clinical immunology.