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Results for “Immune microenvironment”

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PubMed2024

Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy.

Microorganisms in the gut and other niches may contribute to carcinogenesis while also altering cancer immune surveillance and therapeutic response. However, determining the impact of genetic variations and interplay with intestinal microbes' environment is difficult and unanswered. Here, we examined the frequency of thirteen mutant genes that caused aberrant gut in thirty different types of cancer using The Cancer Genomic Atlas (TCGA) database. Substantially, our findings show that all these mutated genes are quite frequent in uterine corpus endometrial cancer (UCEC). Further, these mutant genes are implicated in the infiltration of different subset of immune cells within the Tumor Microenvironment (TME) of UCEC patients. The top-ranking mutant genes that promote immune cell invasion into the TME of UCEC patients were PGLYRP2, OLFM4, and TLR5. In this regard, we used the same deconvolution of the TCGA database to analyze the microbiome that have a strong association with immune cells invasion with TME of UCEC patients. Several bacteria and viruses have been linked to the invasion of immune cells, such as B cell memory and T cell regulatory (Tregs), into the TME of UCEC patients. As a result, our findings pave the way for future research into generating novel immunizations against bacteria or viruses as immunotherapy for UCEC patients.

Humans↗
PubMed2024

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Humans↗
PubMedDate not supplied

Addicted to death: invasive cancer and the immune response to unscheduled cell death.

The development of an invasive cancer involves a progressive switch from predominantly apoptotic (scheduled) to necrotic (unscheduled) tumor cell death. This switch is associated with chronic and increasing release of intracellular factors that in turn promote reactive angiogenesis and stromal proliferation and mediates the disordered tumor microenvironment associated with local immune suppression. The authors review the relevant immunobiology of these factors, including the nuclear protein HMGB1; the products of purine metabolism (uric acid, ATP, and adenosine); the S100 family members; and the heat shock proteins, which we believe drive futile cycles of cell death followed by reparative cell growth. The authors also present a novel and provocative hypothesis that suggests that most of the derangements that we associate with progression of cancer and the associated immunologic consequences can indeed be ascribed to the consequences of disordered tumor cell death rather than cell growth. Thus the fundamental defect in invasive human cancers, in the authors' view, is not one of cell growth but rather one of disordered cell death, resulting in turn in a tumor microenvironment that encourages tumor growth, progression, and local immunosuppression, a condition the authors have termed "addicted to death." This new understanding could inform and drive the development of more effective biologic therapies for patients with cancer.

Apoptosis↗
PubMed1999

Characterization of soluble factors from cultures of premalignant cervical epithelium.

PURPOSE: Immune responses within the cervical microenvironment are likely to play an important role in the natural history of premalignant lesions but the pattern of this response and how it is regulated has not been documented in detail. METHODS: Explants of premalignant cervical epithelium were cultured in vitro for 24 hours. The culture supernatants were assayed for the presence of IL-1alpha, IL-10, IL-12 and TNF-alpha by ELISA. Aliquots of each supernatant were also added to a CD3-dependent T cell proliferation assay. RESULTS: The pattern of cytokines found in different samples was heterogeneous and no significant correlation was observed between the various cytokines examined. The functional effects observed were also diverse, with some supernatants showing strong inhibitory T cell activity, while others were stimulatory. CONCLUSION: Our results document the heterogeneity of the local cytokine microenvironment of premalignant cervical lesions, which may play a role in regulating the immune response associated with such lesions and hence influence clinical outcome.

CD3 Complex↗
PubMed2025

Effect of extracellular vesicles in remodeling the tumor microenvironment by DNMT1 downregulation for enhanced cancer immunotherapy.

BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.

Animals↗
PubMed2026

The mechanism of malignant progression in extramammary Paget's disease (EMPD): hallmarks of EMPD.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Genome mutation↗
PubMed2003

Anatomical basis of tolerance and immunity to intestinal antigens.

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.

Administration, Oral↗
PubMed2003

Influence of CCR7 ligand DNA preexposure on the magnitude and duration of immunity.

The CC chemokine receptor (CCR) 7 ligands CCL21 and CCL19 were recently described as essential elements for establishing the microenvironment needed to initiate optimal immune responses in secondary lymphoid tissues. In the present study we have kinetically investigated the primary responses of naive DO11.10 TCR-transgenic CD4+ T cells (OVA323-339 peptide specific) adoptively transferred into normal BALB/c mice given plasmid DNA encoding CCR7 ligands. The primary responses of CD4+ Tg-T cells in CCR7 ligand DNA recipients occurred more promptly, reaching levels higher than those observed in vector controls. In line with enhanced specific immunity, the T-cell population in CCR7 ligand recipients underwent more in vivo cell division following Ag stimulation, and a higher percentage of Ag-specific T cells expressed an activation phenotype. Moreover, the enhanced primary responses of naive CD4+ T cells appeared to act via affects on migration and maturation of CD11c+ dendritic cells in the draining lymph nodes. In addition following mucosal challenge of herpes simplex virus-immune mice with virus, those that had received CCL21 or CCL19 during priming contained a higher frequency of responding CD4 T cells in lymph nodes and the site of infection. Moreover, CCL21- and CCL19-treated mice showed less severe disease and better survival following challenge. Our results are discussed in terms of the relevance of CCR7 ligand preimmunization to improve vaccine.

Adoptive Transfer↗
PubMed2006

Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.

PURPOSE: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive network that promotes tumor growth and protects the tumor from immune attack. In this study, we examined the contribution of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon. EXPERIMENTAL DESIGN: Expression of IDO was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of 143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical variables. RESULTS: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly dependent on IFN-gamma stimulation. Immunohistochemical scores revealed IDO-high expression in 56 of 143 (39.2%) tumor specimens, whereas 87 of 143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction of CD3+ infiltrating T cells (46.02 +/- 7.25) as compared with tissue samples expressing low IDO (19.42 +/- 2.50; P = 0.0003). Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged as an independent prognostic variable (<45 months, P = 0.006; >45 months, P = 0.04). CONCLUSION: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression and overall survival in patients with colorectal cancer.

CD3 Complex↗
PubMed2001

Expression of cytokine and chemokine genes in Epstein-Barr virus-associated nasopharyngeal carcinoma: comparison with Hodgkin's disease.

Nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD) are characterized by their association with Epstein-Barr virus (EBV) and the presence of an intense lymphoid stroma, consisting of T lymphocytes and other reactive cells. In both entities, the tumour cells express viral proteins known to provide target epitopes for cytotoxic T-cells (CTLs), yet in vivo, the tumour cells appear to escape CTL recognition. A comparative in situ hybridization study of cytokine and chemokine gene expression in NPC and HD has been undertaken, focusing on cytokines which are known to be inducible by EBV in vitro. Hodgkin and Reed-Sternberg (HRS) cells expressed interleukin (IL)-6, IL-8, and IL-10, and the thymus and activation regulated chemokine (TARC) in 15/22, 0/22, 5/22, and 16/21 cases, respectively. In NPC, the epithelial tumour cells showed expression of IL-6 in 3/43 cases and of IL-8 in 2/40 cases. There was no detectable expression of IL-10 and TARC in these cases. These data confirm that HRS cells frequently express cytokine and chemokine genes and suggest that this may enable HRS cells to modulate the immune response in their microenvironment and to escape CTL detection. In contrast, NPC tumour cells show only rare expression of IL-6 and IL-8 and no detectable expression of IL-10 and TARC. Thus, the results suggest that the mechanisms employed by the EBV-positive tumour cells to escape immune recognition and destruction differ between HD and NPC.

Carcinoma↗
PubMed2003

Interleukin-2 and cancer: critical analysis of results, problems and expectations.

The cancer process in a combination of two kinds of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.

Cytokines↗
PubMed2005

Interleukin-10 and the immune response against cancer: a counterpoint.

Although interleukin-10 (IL-10) is commonly regarded as an anti-inflammatory, immunosuppressive cytokine that favors tumor escape from immune surveillance, a wealth of evidence is accumulating that IL-10 also possesses some immunostimulating properties. In fact, IL-10 has the pleiotropic ability of influencing positively and negatively the function of innate and adaptive immunity in different experimental models, which makes it questionable to merely categorize this cytokine as a target of anti-immune escape therapeutic strategies or rather, as an immunological adjuvant in the fight against cancer. Here, we review available data about the immunostimulating anticancer properties of IL-10, and in particular, we focus on the hypothesis that in contrast to what occurs in secondary lymphoid organs, IL-10 overexpression within the tumor microenvironment may catalyze cancer immune rejection.

Adjuvants, Immunologic↗
PubMed2005

Leveraging the activity of tumor vaccines with cytotoxic chemotherapy.

Engaging the power of the patient's own immune system to actively seek out and destroy transformed cells holds great promise for cancer therapy. Tumor vaccines offer the potential for preventing cancer in high-risk individuals, preventing disease relapse after diagnosis and initial therapy, and shifting the balance of the host-tumor interaction to mitigate the progression of advanced cancers. The therapeutic activity of tumor vaccines is limited by the sheer physical burden of the cancer itself, pathways of local immune tolerance and escape active within the tumor microenvironment, and superimposed potent systemic mechanisms of immune tolerance. In this review, we describe how cytotoxic chemotherapy can be integrated with tumor vaccines using unique doses and schedules to break down these barriers, releasing the full potential of the antitumor immune response to eradicate disease.

Animals↗
PubMed2025

Population analysis and immunologic landscape of melanoma in people living with HIV.

PURPOSE: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently exhibited worse clinical outcomes than HIV-negative individuals (PLw/oH) with the same cancer. EXPERIMENTAL DESIGN: We analyzed electronic health records from 1,019 PLWH and 373,121 PLw/oH diagnosed with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), followed by downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). RESULTS: PLWH were diagnosed with melanoma at a younger age, had a higher representation of Hispanic and Black individuals compared to PLw/oH, and a decreased survival rate. PLWH also showed a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse survival outcomes following ICI, even after balancing for demographic covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with upregulation of immune checkpoints (PD1, LAG3) and reduced expression of antigen presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and their microenvironments. Multiplex immunofluorescence confirmed an exhausted CD8+ T cell compartment in PLWH, including enrichment of PD1intLAG3- and PD1intLAG3+ subpopulations, and a significant accumulation of immunosuppressive myeloid-derived suppressor cells (CD11b+ HLA-DR- CD33+). CONCLUSIONS: Our findings suggest chronic HIV infection fosters a permissive tumor microenvironment that might undermine effective immune responses and contribute to poor clinical outcomes for PLWH with melanoma. Targeting the actionable immune pathways identified in this study could inform tailored therapeutic strategies to mitigate these disparities.

HIV↗
PubMed1998

A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation.

There are numerous observations reporting that phagocytes expressing major histocompatibility complex (MHC) Class II molecules are associated with the central nervous system (CNS) in normal and pathological conditions. Although MHC Class II expression is necessary for antigen presentation to CD4 + T-cells, it is not sufficient and co-stimulatory molecules are also required. We review here recent in vivo studies demonstrating that the microglia and perivascular macrophages are unable to initiate a primary immune response in the CNS microenvironment, but may support secondary immune responses. Although in vitro studies show that microglia do not support a primary immune response leading to T-cell proliferation, they do show that microglia may protect the CNS from the unwanted attentions of autoreactive T-cells by inducing their apoptosis. The lack of cells in the CNS parenchyma with the ability to initiate a primary immune response has a cost, namely that pathogens may persist in the CNS undetected by the immune system.

Animals↗
PubMed2003

Therapeutic vaccine to control stromal tumor-induced immunosuppression in human uterine cervixc cancer.

Cancer cells may escape immune surveillance by secreting in their microenvironment soluble factors that may locally paralyze the stromal effector immune cells. In the human uterine cervix cancer, HPV-16 E7 protein, released in the stroma, should contribute to cancer cells immune escape since this protein inhibits the cellular immune response to recall antigens or alloantigens and strongly enhances the release of immunosuppressive cytokines by APCs. This prompted us to prepare a therapeutic vaccine triggering anti-E7 neutralizing Abs to antagonize the E7-induced stromal immunosuppressive effects and allow cellular immune reaction towards cancer cells including specific CTLs, induced by conventional vaccine, to be effective. Since HPV-16 is a mucosotropic virus, this therapeutic vaccine has been prepared to generate systemic as well as mucosal immunity.

Animals↗
PubMed2005

Altered immunity accompanies disease progression in a mouse model of prostate dysplasia.

Increasing evidence suggests that altered immune function accompanies, and indeed may facilitate, cancer progression. In this study, we sought to determine the nature of, and cellular mechanisms underlying, changes in immune status during disease progression in a transgenic mouse model of prostate dysplasia. Immune cells in the tumor microenvironment, as well as in the secondary lymphoid tissues, displayed altered phenotypes. Although evidence of antitumor immunity was detected, there was a paradoxical decrease in the ability of T cells to proliferate in vitro at later stages of disease progression. Detailed analysis of the draining lumbar lymph nodes revealed an increased frequency and number of CD4(+)CD25(+) T cells and an enhanced production of inhibitory cytokines, which correlated with impaired T-cell function. Functional studies confirmed a role for CD4(+)CD25(+) regulatory T cells in suppressing T-cell proliferation as well as regulating the growth of transplanted prostate tumor cells. In addition, our studies show for the first time that anti-CD25 antibody treatment reduces, but does not prevent, tumor growth in a transgenic mouse model of prostate dysplasia. Taken together, this work provides compelling evidence that prostate tumor progression is accompanied by altered immune function and, moreover, that regulatory T cells play an important role in this process. These studies thus provide the impetus for development of specific and effective strategies to deplete regulatory T cells, or suppress their function, as an alternative or adjunct strategy for reducing tumor growth.

Animals↗
PubMed1999

Gene therapy strategies to facilitate organ transplantation.

Organ transplantation is now the definitive therapy for many forms of end-organ disease, but chronic allograft rejection, the side effects of chronic immunosuppressive therapy and the severe donor organ shortage continue to limit its success. Gene therapy has the potential to prevent graft rejection by manipulating the immune response in the microenvironment of the graft or by facilitating the induction of tolerance. Genetic manipulation of stem cells to create transgenic and/or knockout animals that could serve as organ or cell donors could be combined with gene therapy approaches to overcome the problem of limited allogeneic donor organ supply.

Animals↗