Obesity and CD8 T cell metabolism: Implications for anti-tumor immunity and cancer immunotherapy outcomes.

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.

Sequential modulation of the Wnt/ß-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance.

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.

Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.

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 ∼30 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.

Biotinylated Streptavidin Surface Coating Improves the Efficacy of a PLGA Microparticle-Based Cancer Vaccine.

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.

Inverse association between changes in energetic cost of walking and vertical accelerations in non-metastatic breast cancer survivors.

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.

The antitumor effects of entinostat in ovarian cancer require adaptive immunity.

BACKGROUND: Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. In the current study, they evaluated whether entinostat treatment and resultant MHCII expression would enhance beneficial immune responses and impair tumor growth in mice with ovarian cancer. METHODS: C57BL/6 mice bearing intraperitoneal ID8 tumors were randomized to receive entinostat 20 mg/kg daily versus control. Changes in messenger RNA (mRNA) expression of 46 genes important for antitumor immunity were evaluated using NanoString analysis, and multicolor flow cytometry was used to measure changes in protein expression and tumor-infiltrating immune cells. RESULTS: Entinostat treatment decreased the growth of both subcutaneously and omental ID8 tumors and prolonged survival in immunocompetent C57BL/6 mice. NanoString analysis revealed significant changes in mRNA expression in 21 of 46 genes, including increased expression of the MHCI pathway, the MHCII transactivator (CIITA), interferon γ, and granzyme B. C57BL/6 mice that received entinostat had increased MHCII expression on omental tumor cells and a higher frequency of tumor-infiltrating, CD8-positive T cells by flow cytometry. In immunocompromised mice, treatment with entinostat had no effect on tumor size and did not increase MHCII expression. CONCLUSIONS: In the current murine ovarian cancer model, entinostat treatment enhances beneficial immune responses. Moreover, these antitumor effects of entinostat are dependent on an intact immune system. Future studies combining entinostat with checkpoint inhibitors or other immunomodulatory agents may achieve more durable antitumor responses in patients with ovarian cancer.

Ease of walking associates with greater free-living physical activity and reduced depressive symptomology in breast cancer survivors: pilot randomized trial.

PURPOSE: We hypothesized exercise training-induced improvements in ease of walking would associate with favorable changes in objectively measured physical activity (PA) and self-reported depressive symptoms following a PA behavior-change intervention in non-metastatic breast cancer survivors (BCS). METHODS: Twenty-seven BCS received random assignment to an intervention (INT) or control group (CON). INT included counseling/group discussions coupled with supervised exercise tapered to unsupervised exercise. PA, depressive symptoms, and ease of walking were evaluated pre-/post-intervention using 10-day accelerometry, HADS depression subscale, and indirect calorimetry during a standardized treadmill test, respectively. PA composite score was calculated by converting weekly minutes of moderate-to-vigorous PA and average steps/day to z-scores then dividing the sum by 2. Cardiac efficiency was determined by dividing steady-state oxygen uptake by heart rate to evaluate the volume of oxygen consumed per heartbeat. RESULTS: ANCOVA revealed a significant time by group interaction showing the INT group exhibited greater positive changes in the PA composite compared to the CON (INT, + 0.14 ± 0.66 au vs. CON, - 0.48 ± 0.49 au; p = 0.019; η p2 = 0.21). Changes occurring from baseline to follow-up, among all participants, revealed improved ease of walking (less oxygen uptake) associated with increased PA composite (r = - 0.52; p = 0.010) and lower depressive symptomology (r = 0.50; p = 0.012) adjusted for age, race, and months since cancer diagnosis. Increased cardiac efficiency during the standardized treadmill test also associated with less daily sedentary time (r = - 0.52; p = 0.021). CONCLUSIONS: These data support the assertion that reducing the physiological difficulty of walking may contribute to greater engagement in free-living PA, less sedentary time, and decreased psychosocial distress among BCS.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer.

BACKGROUND: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. METHODS: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. RESULTS: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P=0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs -1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P=0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. CONCLUSIONS: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.

Emerging Impact of Malnutrition on Surgical Patients: Literature Review and Potential Implications for Cystectomy in Bladder Cancer.

PURPOSE: Malnutrition is emerging as a significant factor in patient outcomes. A contemporary review of malnutrition has not been performed for the urologist. We review the available literature and current standards of care for malnutrition screening, assessment and intervention, focusing on patients with bladder cancer treated with cystectomy. MATERIALS AND METHODS: Our multidisciplinary team searched PubMed® for available literature on malnutrition, focusing on definition and significance, importance to urologists, screening, assessment, diagnosis, immunological and economic impacts, and interventions. RESULTS: The prevalence of malnutrition in hospitalized patients is estimated to range from 15% to 60%, reaching upward of 71% in those with cancer. Malnutrition has been shown to increase inflammatory markers, further intensifying catabolism and weight loss. Bladder cancer is catabolic and patients undergoing cystectomy have increased resting energy expenditure postoperatively. Data are emerging on the impact of malnutrition in the cystectomy population. Recent studies have identified poor nutritional status based on low albumin or sarcopenia (loss of muscle) as having an adverse impact on length of hospitalization, complications and survival. The current standard of care malnutrition assessment tool, the 2012 consensus statement of the Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition, has not been evaluated in the urological literature. Perioperative immunonutrition in patients undergoing colorectal surgery has been associated with significant decreases in postoperative complications, and recent pilot work has identified the potential for immunonutrition to positively impact the cystectomy population. CONCLUSIONS: Malnutrition has a significant impact on surgical patients, including those with bladder cancer. There are emerging data in the urological literature regarding how best to identify and improve the nutritional status of patients undergoing cystectomy. Additional research is needed to identify malnutrition in these patients and interventions to improve surgical outcomes.

Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors.

U.S. Food and Drug Administration-approved high-dose IL-2 therapy and dendritic cell (DC) immunization offer time-tested treatments for malignancy, but with defined issues of short in vivo t1/2, toxicity, and modest clinical benefit. Complexes of IL-2 with specific mAbs (IL-2c) exhibit improved stability in vivo with reduced toxicity and are capable of stimulating NK cell and memory phenotype CD8 T cell proliferation. In this study, we demonstrate that IL-2c treatment in tumor-bearing mice can enhance NK cell and tumor-specific CD8 T cell numbers. Importantly, DC immunization coupled with stabilized IL-2c infusion drastically improves the tumor-specific effector CD8 T cell response. DC + IL-2c treatment enhances number, 41BB and GITR expression, granzyme B production, CTL/regulatory T cell ratio, and per-cell killing capacity of CD8 T cells without increasing inhibitory molecule expression. Notably, IL-2c treatment of anti-CD3-stimulated human CD8 T cells resulted in higher number and granzyme B production, supporting the translational potential of this immunotherapy strategy for human malignancy. DC + IL-2c treatment enhances both endogenous NK cell and tumor Ag-specific CD8 T cell immunity to provide a marked reduction in tumor burden in multiple models of pre-existing malignancy in B6 and BALB/c mice. Depletion studies reveal contributions from both tumor-specific CD8 T cells and NK cells in control of tumor burden after DC + IL-2c treatment. Together, these data suggest that combination therapy with DC and IL-2c may be a potent treatment for malignancy.

Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review.

OBJECTIVE: Epithelial ovarian cancer continues to be the deadliest gynecologic malignancy. Patients with both diabetes mellitus and obesity have poorer outcomes, yet research correlating metabolic abnormalities, such as metabolic syndrome, to ovarian cancer risk and outcomes is lacking. This article reviews the literature regarding metabolic derangements and their relationship to epithelial ovarian cancer, with a focus on potential mechanisms behind these associations. METHODS: PubMed and Google Scholar were searched for articles in the English language regarding epithelial ovarian cancer, obesity, diabetes mellitus, and metabolic syndrome, with a focus on studies conducted since 1990. RESULTS: Obesity, type II diabetes mellitus, and metabolic syndrome have been associated with poor outcomes in epithelial ovarian cancer. More studies investigating the relationship between metabolic syndrome and epithelial ovarian cancer are needed. A variety of pathologic factors may contribute to cancer risk in patients with metabolic derangements, including altered adipokine and cytokine expression, altered immune responses to tumor cells, and changes in pro-tumorigenic signaling pathways. CONCLUSION: More research is needed to examine the effects of metabolic syndrome on epithelial ovarian cancer risk and mortality, as well as the underlying pathophysiologies in patients with obesity, diabetes mellitus, and metabolic syndrome that may be targeted for therapeutic intervention.

Diet-induced obesity does not impact the generation and maintenance of primary memory CD8 T cells.

The extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses and renders obese individuals susceptible to infection remains unknown. In this study, we show that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells, including acquisition of a long-term memory phenotype (i.e., CD27(hi), CD62L(hi), KLRG1(lo)) and function (i.e., cytokine production, secondary expansion, and memory CD8 T cell-mediated protection). Additionally, obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses in inbred and outbred hosts generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, the rate of naive-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell immunization was similar in lean and obese hosts, suggesting that obesity-associated inflammation, unlike pathogen- or adjuvant-induced inflammation, did not influence the development of endogenous memory CD8 T cell responses. Therefore, our studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established, a surprising notion with important implications for future studies aiming to elucidate the role obesity plays in host susceptibility to infections.

CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma.

Tumor progression occurs through the modulation of a number of physiological parameters, including the development of immunosuppressive mechanisms to prevent immune detection and response. Among these immune evasion mechanisms, the mobilization of myeloid-derived suppressor cells (MDSC) is a major contributor to the suppression of antitumor T-cell immunity. Patients with renal cell carcinoma (RCC) show increased MDSC, and methods are being explored clinically to reduce the prevalence of MDSC and/or inhibit their function. In the present study, we investigated the relationship between MDSC and the therapeutic potential of a TRAIL-encoding recombinant adenovirus (Ad5-TRAIL) in combination with CpG-containing oligodeoxynucleotides (Ad5-TRAIL/CpG) in an orthotopic mouse model of RCC. This immunotherapy effectively clears renal (Renca) tumors and enhances survival, despite the presence of a high frequency of MDSC in the spleens and primary tumor-bearing kidneys at the time of treatment. Subsequent analyses revealed that the CpG component of the immunotherapy was responsible for decreasing the frequency of MDSC in Renca-bearing mice; further, treatment with CpG modulated the phenotype and function of MDSC that remained after immunotherapy and correlated with an increased T-cell response. Interestingly, the CpG-dependent alterations in MDSC frequency and function did not occur in tumor-bearing mice complicated with diet-induced obesity. Collectively, these data suggest that in addition to its adjuvant properties, CpG also enhances antitumor responses by altering the number and function of MDSC.

Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth.

Obesity is a mounting health concern in the United States and is associated with an increased risk for developing several cancers, including renal cell carcinoma (RCC). Despite this, little is known regarding the impact of obesity on antitumor immunity. Because dendritic cells (DC) are critical regulators of antitumor immunity, we examined the combined effects of obesity and tumor outgrowth on DC function. Using a diet-induced obesity (DIO) model, DC function was evaluated in mice bearing orthotopic RCC and in tumor-free controls. Tumor-free DIO mice had profoundly altered serum cytokine and chemokine profiles, with upregulation of 15 proteins, including IL-1α, IL-17, and LIF. Tumor-free DIO mice had elevated percentages of conventional splenic DC that were impaired in their ability to stimulate naive T cell expansion, although they were phenotypically similar to normal weight (NW) controls. In DIO mice, intrarenal RCC tumor challenge in the absence of therapy led to increased local infiltration by T cell-suppressive DC and accelerated early tumor outgrowth. Following administration of a DC-dependent immunotherapy, established RCC tumors regressed in normal weight mice. The same immunotherapy was ineffective in DIO mice and was characterized by an accumulation of regulatory DC in tumor-bearing kidneys, decreased local infiltration by IFN-γ-producing CD8 T cells, and progressive tumor outgrowth. Our results suggest that the presence of obesity as a comorbidity can impair the efficacy of DC-dependent antitumor immunotherapies.

An Exogenous Ketone Ester Slows Tumor Progression in Murine Breast and Renal Cancer Models.

BACKGROUND/OBJECTIVES: Ketone esters (KEs) exhibit promise as anti-cancer agents but their impact on spontaneous metastases remains poorly understood. Although consumption of a ketogenic diet (KD) that is low in carbohydrates and high in fats can lead to KE production in vivo, the restrictive composition of KDs may diminish adherence in cancer patients. METHODS: We investigated the effects of an exogenous ketone ester-supplemented (eKET), carbohydrate-replete diet on tumor growth, metastasis, and underlying mechanisms in orthotopic models of metastatic breast (4T1-Luc) and renal (Renca-Luc) carcinomas. Mice were randomized to diet after tumor challenge. RESULTS: Administration of KEs did not alter tumor cell growth in vitro. However, in mice, our eKET diet increased circulating ß-hydroxybutyrate and inhibited primary tumor growth and lung metastasis in both models. Body composition analysis illustrated the overall safety of eKET diet use, although it was associated with a loss of fat mass in mice with renal tumors. Immunogenetic profiling revealed divergent intratumoral eKET-related changes by tumor type. In mammary tumors, Wnt and TGFß pathways were downregulated, whereas in renal tumors, genes related to hypoxia and DNA damage repair were downregulated. CONCLUSIONS: Thus, our eKET diet exerts potent antitumor and antimetastatic effects in both breast and renal cancer models, albeit with different modes of action and physiologic effects. Its potential as an adjuvant dietary approach for patients with diverse cancer types should be explored further.

Inhibition of the RNA Regulator HuR by SRI-42127 Attenuates Neuropathic Pain After Nerve Injury Through Suppression of Neuroinflammatory Responses.

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.

Re-Evaluating the Effects of Obesity on Cancer Immunotherapy Outcomes in Renal Cancer: What Do We Really Know?

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.

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice.

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.

Diabetes medications as potential calorie restriction mimetics-a focus on the alpha-glucosidase inhibitor acarbose.

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.