ABSTRACT
Parkin is an E3 ubiquitin ligase, which plays a key role in the development of Parkinson disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth, which was associated with poor tumor antigen presentation and limited antitumor CD8+ T-cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced Akt activation. Increased Akt signaling led to dysregulation of antigen presentation, and treatment with the Akt inhibitor MK2206-2HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from patients with clear cell renal cell carcinoma indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer. SIGNIFICANCE: Parkin prevents immune evasion by regulating tumor antigen processing and presentation through the PTEN/Akt network, which has important implications for immunotherapy treatments in patients with Parkin-deficient tumors.
Subject(s)
Antigen Presentation , Neoplasms , Animals , Humans , Mice , Immunotherapy , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/metabolism , Proto-Oncogene Proteins c-akt , Tumor Escape , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
ABSTRACT: It is increasingly recognized that heterogeneities in tumor response and severity of adverse effects in irradiated patients can be attributed to the tumor microenvironment and host-related factors. Among the latter, a growing body of literature in recent years has demonstrated the role of the patient's microbiome in modulating both tumor and normal tissue response to radiotherapy (RT). Upon contact with the environment after birth, the infant's gastrointestinal tract is rapidly colonized by microbiota, which is low in diversity and predominantly characterized by 2 dominant species, Actinobacteria and Proteobacteria. With time, intestinal microbiota diversity increases, and colonization of Firmicutes and Bacteroidetes becomes dominant. By the time a child reaches 3 years, the gut microbiota composition has been reshaped and is relatively similar to that of an adult. The microbiome colonizing the different body organs comprises various species and abundances, which may impact human health. Although the adult microbiome composition is thought to remain stable in health, microbiome diversity and composition respond to different environmental and pathological conditions, including pharmaceutical interventions and RT. Our review focuses on how the gut microbiota modulates normal tissue toxicity and tumor control. Readers who want to learn more about how RT shapes gut microbiome diversity and composition are referred to several excellent recently published reviews.
Subject(s)
Gastrointestinal Microbiome , Microbiota , Adult , Infant , Child , Humans , Firmicutes , Proteobacteria , BacteroidetesABSTRACT
Background and purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Materials and methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred. Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.
ABSTRACT
Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.
Subject(s)
Gastrointestinal Microbiome , Receptors, Chimeric Antigen , Humans , Mice , Animals , Receptors, Antigen, T-Cell/genetics , Cross-Priming , Vancomycin/pharmacology , Immunotherapy , T-Lymphocytes , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/genetics , Antigens, CD19ABSTRACT
BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.
Subject(s)
Colitis , Melanoma , Colitis/chemically induced , Colitis/complications , Colitis/drug therapy , Humans , Ipilimumab/adverse effects , Melanoma/therapy , Retrospective Studies , Steroids/therapeutic useABSTRACT
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.
Subject(s)
Gastrointestinal Microbiome , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Antigens, CD19 , Humans , Immunotherapy, Adoptive/adverse effects , Neurotoxicity Syndromes/etiology , Prospective Studies , Retrospective StudiesABSTRACT
BACKGROUND: Tumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade. METHODS: Mice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments. RESULTS: We demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy. CONCLUSION: Our findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.
Subject(s)
Antigens, CD/metabolism , Colorectal Neoplasms/therapy , Immune Checkpoint Inhibitors/administration & dosage , Lung Neoplasms/therapy , Neoplasm Proteins/metabolism , Vaccines, DNA/administration & dosage , Adenoviridae/genetics , Animals , Cancer Vaccines/administration & dosage , Cancer Vaccines/pharmacology , Cell Line, Tumor , Colorectal Neoplasms/diagnostic imaging , Combined Modality Therapy , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/diagnostic imaging , Mice , Radiation Dose Hypofractionation , Treatment Outcome , Ultrasonography, Doppler , Vaccines, DNA/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided. RESULTS: There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P <.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR = 2.78, 95% CI = 1.31 to 5.87; P =.007). When limited to only patients who received adjuvant ICI (n = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR = 4.84, 95% CI = 1.09 to 21.50; P =.04). The antibiotic group had a greater incidence of colitis (HR = 2.14, 95% CI = 1.02 to 4.52; P =.046). CONCLUSION: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.
Subject(s)
Anti-Bacterial Agents/adverse effects , Gastrointestinal Microbiome/genetics , Genetic Variation/drug effects , Melanoma/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Disease-Free Survival , Female , Gastrointestinal Microbiome/drug effects , Genetic Variation/genetics , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immunologic Factors/antagonists & inhibitors , Immunologic Factors/genetics , Immunotherapy/adverse effects , Male , Melanoma/microbiology , Melanoma/mortality , Melanoma/pathology , Middle Aged , Neoplasm Staging , Young AdultABSTRACT
BACKGROUND: Novel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC. METHODS: Using the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry. RESULTS: We demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid. CONCLUSIONS: Ascites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.
Subject(s)
Ascites/physiopathology , Cancer Vaccines/immunology , Monocytes/metabolism , Ovarian Neoplasms/immunology , Toll-Like Receptors/immunology , Animals , Female , Humans , Mesothelin , Mice , Ovarian Neoplasms/mortality , Survival AnalysisABSTRACT
Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2-tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell-mediated manner. Combination of anti-PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.
Subject(s)
Cancer Vaccines/pharmacology , Forkhead Box Protein L2/immunology , Granulosa Cell Tumor/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Adult , Animals , Cancer Vaccines/immunology , Cell Line, Tumor , Epitopes , Female , Forkhead Box Protein L2/genetics , Forkhead Box Protein L2/metabolism , Granulosa Cell Tumor/pathology , Granulosa Cell Tumor/therapy , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Tolerance/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Mice, Inbred Strains , Middle Aged , Pregnancy , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Tumor Microenvironment , Vaccines, DNA/immunology , Vaccines, DNA/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
We explore a novel strategy of activating immune signaling through increased micronuclei formation utilizing a cell cycle checkpoint inhibitor to drive cell cycle progression following ionizing radiation. The Chk1/2 inhibitor AZD7762 is used to abrogate radiation therapy (RT)-induced G2/M cell cycle arrest in multiple cell lines and, we find that this therapeutic combination promotes increased micronuclei formation in vitro and subsequently drives increased type I interferon signaling and cytotoxic T-cell activation. In vivo studies using B16-F10 melanoma cancer cells implanted in C57/BL6 mice demonstrate improved rates of tumor control at the abscopal (unirradiated) site, located outside of the radiation field, only in the AZD7762 + RT group, with a corresponding reduction in mean tumor volume, increase in the CD8 T-cell population, and immune activated gene signaling. Our results demonstrate that targeted inhibition of cell cycle checkpoint activation following ionizing radiation drives increased production of immunogenic micronuclei, leading to systemic tumor response with potential future clinical benefit.
Subject(s)
Cell Nucleus/drug effects , Cell Nucleus/radiation effects , Checkpoint Kinase 1/antagonists & inhibitors , Checkpoint Kinase 2/antagonists & inhibitors , G2 Phase Cell Cycle Checkpoints/drug effects , G2 Phase Cell Cycle Checkpoints/radiation effects , Melanoma, Experimental/immunology , Neoplasm Proteins/antagonists & inhibitors , Thiophenes/pharmacology , Urea/analogs & derivatives , Animals , Cell Line, Tumor , Female , Humans , Interferon-beta/biosynthesis , Interferon-beta/genetics , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Melanoma, Experimental/radiotherapy , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Mice, Inbred C57BL , Micronucleus Tests , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , STAT1 Transcription Factor/biosynthesis , STAT1 Transcription Factor/genetics , Tumor Burden/drug effects , Tumor Burden/radiation effects , Urea/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.
Subject(s)
Antigen Presentation/radiation effects , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Gastrointestinal Microbiome , Neoplasms, Experimental , Animals , Antigen Presentation/genetics , Antigens, Neoplasm/genetics , Butyrates/immunology , CD8-Positive T-Lymphocytes/pathology , Dendritic Cells/pathology , Female , Gastrointestinal Microbiome/immunology , Gastrointestinal Microbiome/radiation effects , Mice , Mice, Knockout , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Neoplasms, Experimental/radiotherapyABSTRACT
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Chemotaxis, Leukocyte , Cytokines/metabolism , Dendritic Cells/metabolism , Lymphocyte Activation , Lymphocytes, Tumor-Infiltrating/metabolism , Macrophages/metabolism , Ovarian Neoplasms/metabolism , Animals , Antineoplastic Agents, Immunological/pharmacology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CCL5/metabolism , Chemokine CXCL9/genetics , Chemokine CXCL9/immunology , Chemokine CXCL9/metabolism , Chemotaxis, Leukocyte/drug effects , Coculture Techniques , Cytokines/genetics , Cytokines/immunology , DNA Methylation , Dendritic Cells/drug effects , Dendritic Cells/immunology , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Humans , Immunotherapy/methods , Interferon-gamma/genetics , Interferon-gamma/immunology , Interferon-gamma/metabolism , Lymphocyte Activation/drug effects , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Macrophages/drug effects , Macrophages/immunology , Mice, Inbred C57BL , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Paracrine Communication , Receptors, CXCR3/genetics , Receptors, CXCR3/immunology , Receptors, CXCR3/metabolism , Signal TransductionABSTRACT
The clear cell subtype of kidney cancer encompasses most renal cell carcinoma cases and is associated with the loss of von Hippel-Lindau gene function or expression. Subsequent loss or mutation of the other allele influences cellular stress responses involving nutrient and hypoxia sensing. Autophagy is an important regulatory process promoting the disposal of unnecessary or degraded cellular components, tightly linked to almost all cellular processes. Organelles and proteins that become damaged or that are no longer needed in the cell are sequestered and digested in autophagosomes upon fusing with lysosomes, or alternatively, released via vesicular exocytosis. Tumor development tends to disrupt the regulation of the balance between this process and apoptosis, permitting prolonged cell survival and increased replication. Completed trials of autophagic inhibitors using hydroxychloroquine in combination with other anticancer agents including rapalogues and high-dose interleukin 2 have now been reported. The complex nature of autophagy and the unique biology of clear cell renal cell carcinoma warrant further understanding to better develop the next generation of relevant anticancer agents.
Subject(s)
Autophagy , Carcinoma, Renal Cell/metabolism , Endothelium/metabolism , Kidney Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Autophagy/drug effects , Autophagy/genetics , Biomarkers , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/etiology , Carcinoma, Renal Cell/pathology , Clinical Trials as Topic , Cytoskeleton/metabolism , Disease Susceptibility , Drug Discovery , Drug Screening Assays, Antitumor , Endothelium/drug effects , Endothelium/pathology , High-Throughput Nucleotide Sequencing , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/etiology , Kidney Neoplasms/pathology , Mitochondria/drug effects , Mitochondria/genetics , Mitochondria/metabolism , Mitophagy/drug effects , Mitophagy/genetics , Molecular Imaging , Molecular Targeted Therapy , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolismABSTRACT
An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce "metabolic anergy" of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system.
Subject(s)
Immunotherapy , Mitochondria/metabolism , Neoplasms/immunology , Neoplasms/therapy , Animals , DNA, Mitochondrial/genetics , Humans , Mitochondrial Dynamics , T-Lymphocytes/metabolismABSTRACT
Angiogenesis is a hallmark of cancer and a requisite that tumors must achieve to fulfill their metabolic needs of nutrients and oxygen. As a critical step in cancer progression, the 'angiogenic switch' allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic progression and dissemination. Tumor-dependent triggering of the angiogenic switch has critical consequences on tumor progression which extends from an increased nutrient supply and relies instead on the ability of the tumor to hijack the host immune response for the generation of a local immunoprivileged microenvironment. Tumor angiogenic-mediated establishment of endothelial anergy is responsible for this process. However, tumor endothelium can also promote immune tolerance by unbalanced expression of co-stimulatory and co-inhibitory molecules and by releasing soluble factors that restrain T cell function and induce apoptosis. In this review, we discuss the molecular properties of the tumor endothelial barrier and endothelial anergy and discuss the main immunosuppressive mechanisms triggered by the tumor endothelium. Lastly, we describe the current anti-angiogenic therapeutic landscape and how targeting tumor angiogenesis can contribute to improve clinical benefits for patients.
Subject(s)
Endothelial Cells/physiology , Neoplasms/immunology , Neovascularization, Pathologic , Angiogenesis Inhibitors/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Cell Transformation, Neoplastic , Humans , Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.
Subject(s)
Dendritic Cells/immunology , Gastrointestinal Microbiome/immunology , Hematopoietic Stem Cell Transplantation , Host Microbial Interactions/immunology , Immunotherapy, Adoptive/methods , Interleukin-12/immunology , Neoplasms/therapy , Adult , Aged , Animals , Bacteria/drug effects , Bacteria/genetics , Bacteria/immunology , Bacteria/isolation & purification , CD8 Antigens/immunology , CD8 Antigens/metabolism , Cell Line, Tumor/transplantation , Cohort Studies , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Disease Models, Animal , Fecal Microbiota Transplantation , Female , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/genetics , Host Microbial Interactions/drug effects , Humans , Interleukin-12/antagonists & inhibitors , Interleukin-12/genetics , Interleukin-12/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Neomycin/administration & dosage , Neoplasms/immunology , Neoplasms/microbiology , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Treatment Outcome , Vancomycin/administration & dosageABSTRACT
We investigated the mechanisms by which CD8+ T-cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8+ T-cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). Maternal CD8+ T cells were depleted with anti-CD8+ antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan® gene assays, and neurobehavioral tests. DEP did not significantly prevent LPS-induced preterm birth but improved neurobehavioral performance (P < .001) and increased cortical neuronal density (P < .05) in LPS-exposed pups compared to controls. These changes were associated with decreased CCL3 and CXCL10 and increased CCL5 in DEP LPS-exposed mice. We demonstrate that DEP reduces perinatal brain injury following IUI. This supports a role for maternal CD8+ T-cell trafficking in placenta in mediating perinatal brain injury separate from preterm birth mechanisms.