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Microglial activation with the production of pro-inflammatory mediators such as IL-6, TNF-α, and IL-1ß, is a major driver of neuropathic pain (NP) following peripheral nerve injury. We have previously shown that the RNA binding protein, HuR, is a positive node of regulation for many of these inflammatory mediators in glia and that its chemical inhibition or genetic deletion attenuates their production. In this report, we show that systemic administration of SRI-42127, a novel small molecule HuR inhibitor, attenuates mechanical allodynia, a hallmark of NP, in the early and chronic phases after spared nerve injury in male and female mice. Flow cytometry of lumbar spinal cords in SRI-42127-treated mice shows a reduction in infiltrating macrophages and a concomitant decrease in microglial populations expressing IL-6, TNF-α, IL-1ß, and CCL2. Immunohistochemistry, ELISA, and qPCR of lumbar spinal cord tissue indicate suppression of these cytokines and other inflammatory mediators. ELISA of plasma samples in the acute phase also shows attenuation of inflammatory responses. In summary, inhibition of HuR by SRI-42127 leads to the suppression of neuroinflammatory responses and allodynia after nerve injury and represents a promising new direction in the treatment of NP.
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Neuralgia , Traumatismos del Sistema Nervioso , Ratones , Masculino , Femenino , Animales , Factor de Necrosis Tumoral alfa/metabolismo , ARN/metabolismo , Interleucina-6/metabolismo , Modelos Animales de Enfermedad , Neuralgia/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Microglía/metabolismo , Médula Espinal/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismoRESUMEN
BACKGROUND: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/ß-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/ß-catenin modulation facilitates a more immunotherapy-favorable TME. METHODS: Human tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/ß-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing. RESULTS: DKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights. CONCLUSIONS: Wnt/ß-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy.
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Antineoplásicos/farmacología , Neoplasias de los Genitales Femeninos/genética , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Genes MHC Clase I/genética , Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Femeninos/terapia , Humanos , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Obesity has reached global epidemic proportions and its effects on interactions between the immune system and malignancies, particularly as related to cancer immunotherapy outcomes, have come under increasing scrutiny. Although the vast majority of pre-clinical murine studies suggest that host obesity should have detrimental effects on anti-tumor immunity and cancer immunotherapy outcomes, the opposite has been found in multiple retrospective human studies. As a result, acceptance of the "obesity paradox" paradigm, wherein obesity increases cancer risk but then improves patient outcomes, has become widespread. However, results to the contrary do exist and the biological mechanisms that promote beneficial obesity-associated outcomes remain unclear. Here, we highlight discrepancies in the literature regarding the obesity paradox for cancer immunotherapy outcomes, with a particular focus on renal cancer. We also discuss multiple factors that may impact research findings and warrant renewed research attention in future studies. We propose that specific cancer patient populations may be affected in fundamentally different ways by host obesity, leading to divergent effects on anti-tumor immunity and/or immunotherapy outcomes. Continued, thoughtful analysis of this critical issue is therefore needed to permit a more nuanced understanding of the complex effects of host obesity on cancer immunotherapy outcomes in patients with renal cancer or other malignancies.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias Renales/terapia , Obesidad/inmunología , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Neoplasias Renales/inmunología , Neoplasias Renales/mortalidad , Obesidad/mortalidad , Supervivencia sin Progresión , Factores de Riesgo , Resultado del Tratamiento , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
Associations between modifiable factors and the efficacy of cancer immunotherapies remain uncertain. We found previously that diet-induced obesity (DIO) reduces the efficacy of an immunotherapy consisting of adenovirus-encoded TRAIL plus CpG oligonucleotide (AdT/CpG) in mice with renal tumors. To eliminate confounding effects of diet and determine whether outcomes could be improved in DIO mice, we evaluated AdT/CpG combined with anti-CTLA-4 in diet-matched, obese-resistant (OB-RES) versus DIO tumor-bearing mice. Therapy-treated OB-RES mice displayed effective renal tumor control and sustained CD4+ and CD8+ T cell responses. In contrast, therapy-treated DIO mice exhibited progressive tumor outgrowth and blunted T cell responses, characterized by reduced intratumoral frequencies of IFNγ+ CD4+ and CD8+ T cells. Weak effector T cell responses in therapy-treated DIO mice were accompanied by low intratumoral concentrations of the T cell chemoattractant CCL5, heightened concentrations of pro-tumorigenic GM-CSF, and impaired proliferative capacity of CD44+CD8+ T cells in tumor-draining lymph nodes. Our findings demonstrate that in lean mice with renal tumors, combining in situ T cell priming upstream of anti-CTLA-4 enhances outcomes versus anti-CTLA-4 alone. However, host obesity is associated with heightened immunotherapy resistance, characterized by multi-factorial deficiencies in effector CD4+ and CD8+ T cell responses that extend beyond the tumor microenvironment.
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The immunosuppressive effects of TGFß promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53-/- tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFß ligands was used to neutralize TGFß. Ascites and omentum were collected and changes in T-cell response were measured using flow. Treatment with anti-TGFß therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 mL vs. 0.7 mL; P < 0.001) and improved the CD8:Treg ratio (0.37 vs. 2.5; P = 0.02) compared with untreated mice. A single dose of therapy prior to tumor challenge resulted in a similar reduction of ascites volume (2.7 vs. 0.67 mL; P = 0.002) and increased CD8:Tregs ratio (0.36 vs. 1.49; P = 0.007), while also significantly reducing omental weight (114.9 mg vs. 93.4 mg; P = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 days vs. 57.5 days). TGFß neutralization results in favorable changes to the T-cell response within the tumor microenvironment, leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGFß therapy may be an option for management in patients with ovarian cancer to improve clinical outcomes and warrants further investigation.
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Neoplasias Ováricas/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Análisis de Supervivencia , TransfecciónRESUMEN
The field of aging research has grown rapidly over the last half-century, with advancement of scientific technologies to interrogate mechanisms underlying the benefit of life-extending interventions like calorie restriction (CR). Coincident with this increase in knowledge has been the rise of obesity and type 2 diabetes (T2D), both associated with increased morbidity and mortality. Given the difficulty in practicing long-term CR, a search for compounds (CR mimetics) which could recapitulate the health and longevity benefits without requiring food intake reductions was proposed. Alpha-glucosidase inhibitors (AGIs) are compounds that function predominantly within the gastrointestinal tract to inhibit α-glucosidase and α-amylase enzymatic digestion of complex carbohydrates, delaying and decreasing monosaccharide uptake from the gut in the treatment of T2D. Acarbose, an AGI, has been shown in pre-clinical models to increase lifespan (greater longevity benefits in males), with decreased body weight gain independent of calorie intake reduction. The CR mimetic benefits of acarbose are further supported by clinical findings beyond T2D including the risk for other age-related diseases (e.g., cancer, cardiovascular). Open questions remain regarding the exclusivity of acarbose relative to other AGIs, potential off-target effects, and combination with other therapies for healthy aging and longevity extension. Given the promising results in pre-clinical models (even in the absence of T2D), a unique mechanism of action and multiple age-related reduced disease risks that have been reported with acarbose, support for clinical trials with acarbose focusing on aging-related outcomes and incorporating biological sex, age at treatment initiation, and T2D-dependence within the design is warranted.
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Acarbosa , Diabetes Mellitus Tipo 2 , Acarbosa/uso terapéutico , Restricción Calórica , Diabetes Mellitus Tipo 2/prevención & control , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Longevidad , MasculinoRESUMEN
Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.
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Nearly 70% of adults in the US are currently overweight or obese. Despite such high prevalence, the impact of obesity on antitumor immunity and immunotherapy outcomes remains incompletely understood, particularly in patients with breast cancer. Here, we addressed these gaps in knowledge using two murine models of breast cancer combined with diet-induced obesity. We report that obesity increases CXCL1 concentrations in the mammary tumor microenvironment, driving CXCR2-mediated chemotaxis and accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs) expressing Fas ligand (FasL). Obesity simultaneously promotes hyperactivation of CD8 tumor-infiltrating lymphocytes (TILs), as evidenced by increased expression of CD44, PD-1, Ki-67, IFNγ, and the death receptor Fas. Accordingly, G-MDSCs induce Fas/FasL-mediated apoptosis of CD8 T cells ex vivo and in vivo. These changes promote immunotherapy resistance in obese mice. Disruption of CXCR2-mediated G-MDSC chemotaxis in obese mice is sufficient to limit intratumoral G-MDSC accumulation and improve immunotherapy outcomes. The translational relevance of our findings is demonstrated by transcriptomic analyses of human breast tumor tissues, which reveal positive associations between CXCL1 expression and body mass index, poor survival, and a MDSC gene signature. Further, this MDSC gene signature is positively associated with FASLG expression. Thus, we have identified a pathway wherein obesity leads to increased intratumoral CXCL1 concentrations, which promotes CXCR2-mediated accumulation of FasL+ G-MDSCs, resulting in heightened CD8 TIL apoptosis and immunotherapy resistance. Disruption of this pathway may improve immunotherapy outcomes in patients with breast cancer and obesity.
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Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Mamarias Experimentales/inmunología , Células Supresoras de Origen Mieloide/inmunología , Obesidad/inmunología , Adenoviridae/genética , Animales , Apoptosis , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Inmunoterapia , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/terapia , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/administración & dosificación , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/inmunologíaRESUMEN
BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.
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Ayuno , Neoplasias Renales/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Humanos , Inmunoterapia/efectos adversos , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Obesidad/complicaciones , Obesidad/genéticaRESUMEN
Triple-negative breast cancer (TNBC) is an immune-enriched subset of breast cancer that has recently demonstrated clinical responsiveness to combinatorial immunotherapy. However, the lack of targeted interventions against hormone receptors or HER2 continues to limit treatment options for these patients. To begin expanding available interventions for patients with metastatic TNBC, we previously reported a therapeutic vaccine regimen that significantly reduced spontaneous lung metastases in a preclinical TNBC model. This heterologous vaccine approach "primed" mice with tumor lysate antigens encapsulated within poly(lactic-co-glycolic) acid microparticles (PLGA MPs), and then "boosted" mice with tumor lysates plus adjuvant. The use of the PLGA MP prime as monotherapy demonstrated no efficacy, suggesting that improving this component of our therapy would achieve greater vaccine efficacy. Here, we functionally improved the PLGA MP prime by coating microparticles with biotinylated streptavidin-conjugated using 1-ethyl-3-(3-dimethylaminoproplyl) carbodiimide/N-hydroxysuccinimide (EDC/Sulfo-NHS) linkers. This modification enhanced the immunostimulatory potential of our PLGA MPs, as evidenced by increased phagocytosis, maturation, and stimulatory ligand expression by antigen-presenting cells (APCs). Therapeutic prime/boost vaccination of TNBC-bearing mice with surfaced-coated PLGA MPs significantly reduced spontaneous lung metastases by an average of 56% relative to mice primed with unmodified PLGA MPs, and a significant 88% average reduction in spontaneous lung metastases relative to untreated control mice. These findings illustrate that relatively common biotin-streptavidin conjugation formulations can positively affect microparticle-based vaccine immunogenicity resulting in enhanced therapeutic efficacy against established preclinical mammary tumors.
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Adyuvantes Inmunológicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Estreptavidina/uso terapéutico , Neoplasias de la Mama Triple Negativas/prevención & control , Adyuvantes Inmunológicos/química , Animales , Biotinilación , Vacunas contra el Cáncer/química , Portadores de Fármacos/química , Portadores de Fármacos/uso terapéutico , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/uso terapéutico , Estreptavidina/química , Neoplasias de la Mama Triple Negativas/inmunologíaRESUMEN
Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.
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Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Renales/inmunología , Neoplasias Renales/inmunología , Monocitos/inmunología , Obesidad/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/patología , Estudios de Cohortes , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/patología , Linfocitos T Reguladores/patología , Adulto JovenAsunto(s)
Adiposidad , Neoplasias , Tejido Adiposo , Humanos , Inmunoterapia , Neoplasias/terapia , ObesidadRESUMEN
BACKGROUND: The Wnt/ß-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. METHODS: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and ß-TCR repertoire analysis were used to determine the immune response. RESULTS: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. CONCLUSIONS: These findings suggest that inhibiting the Wnt/ß-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel.
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Obesity is an established risk factor for many cancers and has recently been found to alter the efficacy of T cell-based immunotherapies. Currently, however, the effects of obesity on immunometabolism remain unclear. Understanding these associations is critical, given the fact that T cell metabolism is tightly linked to effector function. Thus, any obesity-associated changes in T cell bioenergetics are likely to drive functional changes at the cellular level, alter the metabolome and cytokine/chemokine milieu, and impact cancer immunotherapy outcomes. Here, we provide a brief overview of T cell metabolism in the presence and absence of solid tumor growth and summarize current literature regarding obesity-associated changes in T cell function and bioenergetics. We also discuss recent findings related to the impact of host obesity on cancer immunotherapy outcomes and present potential mechanisms by which T cell metabolism may influence therapeutic efficacy. Finally, we describe promising pharmaceutical therapies that are being investigated for their ability to improve CD8 T cell metabolism and enhance cancer immunotherapy outcomes in patients, regardless of their obesity status.
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Linfocitos T CD8-positivos/metabolismo , Metabolismo Energético , Obesidad/inmunología , Obesidad/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Manejo de la Enfermedad , Progresión de la Enfermedad , Metabolismo Energético/efectos de los fármacos , Glucólisis , Humanos , Inmunidad Celular , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Neoplasias/complicaciones , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/terapia , Obesidad/complicaciones , Pronóstico , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
In ovarian cancer, upregulation of the Wnt/ß-catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/ß-catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked ß-catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/ß-catenin pathway are dependent on CD8+ T cells, we injected ID8 cells into mice with CD8+ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked ß-catenin specifically in DCs. When CD8+ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/ß-catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8+ T cells.
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The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates invasive phenotypes and suppresses tumor progression in vivo. In contrast, collagens produced by RCC cells promote invasive and migratory phenotypes. PGC1α restoration suppresses the expression of collagens and tumor phenotypes via the induction of miR-29a. Furthermore, decreased collagens via the PGC1α/miR-29a axis suppresses collagen-mediated activation of discoidin domain receptor 1 (DDR1)/ERK signaling. In turn, the suppression of collagen/DDR1 signaling by PGC1α leads to decreased levels of the known EMT regulators SNAIL1 and 2. Collectively, our results demonstrate a novel role for PGC1α in the regulation of proinvasive SNAIL proteins.
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Carcinoma de Células Renales/patología , Colágeno/metabolismo , Neoplasias Renales/patología , MicroARNs/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Factores de Transcripción de la Familia Snail/genética , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Estabilidad Proteica , Factores de Transcripción de la Familia Snail/metabolismoRESUMEN
Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery â¼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1ß, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.
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Neoplasias de la Mama/complicaciones , Restricción Calórica/métodos , Terapia por Ejercicio/métodos , Obesidad/complicaciones , Obesidad/dietoterapia , Biomarcadores/sangre , Composición Corporal , Consejo/métodos , Femenino , Humanos , Sobrepeso/complicaciones , Sobrepeso/dietoterapia , Pérdida de Peso/fisiologíaRESUMEN
BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.
Asunto(s)
Inmunoterapia/métodos , Neoplasias Renales/tratamiento farmacológico , Obesidad/complicaciones , Animales , Femenino , Humanos , Neoplasias Renales/inmunología , Masculino , Ratones , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
PURPOSE: With accelerometry, the utility to detect changes in physical activity are predicated on the assumption that walking energetics and gait mechanics do not change. The present work examined associations between changes (∆) in walking energetics, exercise self-efficacy, and several accelerometer-derived metrics. METHODS: Secondary analyses were performed among a sub-sample (n = 29) of breast cancer survivors participating in a larger randomized trial. During 4 min of treadmill walking (0.89 m s-1, 0% grade), indirect calorimetry quantified steady-state energy expenditure (EE), wherein, participants were fitted with a heart rate monitor and hip-worn triaxial accelerometer. Exercise self-efficacy was measured using a 9-item questionnaire, while vector magnitude (VM) and individual planes (e.g., mediolateral, vertical, and anteroposterior) of the movement were extracted for data analyses. Evaluations were made at baseline and after 3 months. RESULTS: From baseline to 3 months, the energetic cost of walking (kcals min-1) significantly decreased by an average of - 5.1% (p = 0.001; d = 0.46). Conversely, VM significantly increased (p = 0.007; d = 0.53), exclusively due to greater vertical accelerations (acc) (+ 5.7 ± 7.8 acc; p = 0.001; d = 0.69). Changes in vertical accelerations were inversely and positively associated with ∆walking EE (r = - 0.37; p = 0.047) and ∆exercise self-efficacy (r = 0.39; p = 0.034), respectively. CONCLUSION: Hip-worn accelerometers do not appear well-suited to correctly detect changes in ease of walking as evidenced by reduced energetic cost. Further research should determine if a divergence between measured EE and vertical accelerations could contribute to erroneous inferences in free-living physical activity.
Asunto(s)
Neoplasias de la Mama/fisiopatología , Metabolismo Energético/fisiología , Caminata/fisiología , Aceleración , Acelerometría/métodos , Supervivientes de Cáncer , Ejercicio Físico/fisiología , Prueba de Esfuerzo/métodos , Femenino , Marcha/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Persona de Mediana Edad , Actividad Motora/fisiologíaRESUMEN
There is growing interest in harnessing lifestyle and pharmaceutical interventions to boost immune function, reduce tumor growth, and improve cancer treatment efficacy while reducing treatment toxicity. Interventions targeting glucose metabolism are particularly promising, as they have the potential to directly inhibit tumor cell proliferation. However, because anti-tumor immune effector cells also rely on glycolysis to sustain their clonal expansion and function, it remains unclear whether glucose-modulating therapies will support or hinder anti-tumor immunity. In this perspective, we summarize a growing body of literature that evaluates the effects of intermittent fasting, calorie restriction mimetics, and anti-hyperglycemic agents on anti-tumor immunity and immunotherapy outcomes. Based on the limited data currently available, we contend that additional pre-clinical studies and clinical trials are warranted to address the effects of co-administration of anti-hyperglycemic agents or glucose-lowering lifestyle modifications on anti-tumor immunity and cancer treatment outcomes. We stress that there is currently insufficient evidence to provide recommendations regarding these interventions to cancer patients undergoing immunotherapy. However, if found to be safe and effective in clinical trials, interventions targeting glucose metabolism could act as low-cost combinatorial adjuvants for cancer patients receiving immune checkpoint blockade or other immunotherapies.