Although TNBC might be the least “immunologically cold” breast cancer subtype, many factors can still contribute to dampening anti-tumor immunity and immunotherapy efficacy. doi: 10.1038/nrc3967, 18. Found insideThis essential book comprehensively covers the diagnosis, treatment and management of cardiovascular disease in obese patients, translating up-to-date clinical research findings into clinical practice. A clinical trial using Zoledronate, a Vγ9Vδ2 T cell agonist, along with low-dose IL-2 demonstrated improved clinical outcome in metastatic breast cancer patients with a sustained population of mature Vγ9Vδ2 T cells (40). A number of mechanisms have been postulated to support the existence of obesity paradox; however, marked heterogeneity was found across studies and this has cast … Found insideWe hope that this book will be useful for researchers in biomedicine, and also for physicians interested in finding the root causes of the disease, as well as for post-graduate students in biochemistry, molecular biology, nutrition or ... While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. We do not retain these email addresses. Han JM, Patterson SJ, Speck M, Ehses JA, Levings MK. (2010) 285:6153–60. Obesity is a growing global health concern and contributes to ~30% cancer-related mortality, … doi: 10.1038/oby.2008.565, 53. Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, et al. In addition, murine models should further explore the molecular mechanisms by which obesity can affect anti-tumor immunity and efficacy of immune checkpoint inhibitors. (2019) 442:409–28. Cancer Res; 78(8); 1898–903. It is important to note that such hormone and adipokine imbalances can collectively promote mitogenic and mutagenic pathways, leading to an increased risk of cancer (17). This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. We have just begun to look into the question of the optimal body composition and body weight for cancer survivors. doi: 10.1172/JCI99317, 57. This work engages the expertise of a multidisciplinary research team to collate and review the latest knowledge and developments in this exciting research field. AN drafted the manuscript and designed the figures and tables. J Clin Oncol. Immunotherapy for breast cancer: what are we missing? The efficacy of immuno-based interventions varies across cancer types and patient cohorts, which is attributed to a variety of lifestyle, clinical, and pathological factors. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. In line with this, NK-markers of cytotoxicity such as TNF-related apoptosis-inducing ligand (TRAIL) and CD107a are reduced (54). Of note, no increase in irAEs was observed, suggesting that obesity could be safely used as a biomarker to stratify patients for treatment with checkpoint inhibitors. 2 Division of Oncology, Rambam Health Care Campus, Haifa, Israel. (2018) 11:686–90. Overall, this volume will provide important insight to help understand how inflammation may help modulate the linkage between obesity and cancer and serve as a platform for developing future research in this area. A number of recent studies have reported on the obesity paradox in kidney cancer, with the finding that obese people appear to be at higher risk for developing kidney cancer but at a lower risk of dying from kidney cancer. doi: 10.4049/jimmunol.1502570, 47. Patients with a decline in the number of Vγ9Vδ2 T cells experienced a worse outcome, which could be related to γδ T cell anergy or to an increased polarization into immunosuppressive γδ T cells. Oncotarget. Obesity and adverse breast cancer risk and outcome: mechanistic insights and strategies for intervention. Tavazoie MF, Pollack I, Tanqueco R, Ostendorf BN, Reis BS, Gonsalves FC, et al. There are significant heterogeneities across studies in many aspects, including study population, degree of control for confounding, and the length of follow-up. (2012) 189:1311–21. BMJ. ... and lower risks of 9 out of the leading 15 causes of death—notably less cancer and heart disease. There is an emerging scientific concept that there are “metabolically healthy” and “unhealthy” types of obesity, and researchers want to understand if there could be an ideal weight for cancer patients. This review discusses possible explanations for the obesity paradox, the prevalence and consequences of low muscle mass in cancer patients, and future research directions. Toor SM, Syed Khaja AS, El Salhat H, Faour I, Kanbar J, Quadri AA, et al. Studies using computed tomography (CT) images showed that there was a high variability in fat mass and muscle mass within all strata of BMI in cancer patients (46–50). Breast cancer progression is associated with impaired NK cytotoxicity via downregulation of activating receptors (NKG2D, DNAM-1, CD16, CD69) and upregulation of inhibitory receptors (NKG2A) (47). In addition, it would be of interest to investigate whether intervention for obesity-associated hormone imbalances in combination with MDSC-targeting drugs could enhance anti-tumor immunity. (2017) 163:21–35. Several meta-analyses were conducted to quantitatively summarize existing evidence on obesity and cancer survival (11, 12, 81, 82). On the other hand, he said, the findings might reflect some interaction between cancer chemotherapy and other medications. Obesity increases the risk of developing kidney cancer. 6, 7 Others acknowledge that in patient populations, a metabolically healthy obese phenotype that compares favorably to leaner, … doi: 10.1007/s12026-018-8989-4, 54. Characteristics of study population such as race/ethnicity, socioeconomic status, and prevalence of smoking, comorbidities, and other potential confounders also differed across studies. Immune modulations in obesity and in cancer. This review discusses possible explanations for the obesity paradox, the prevalence and consequences of low muscle mass in cancer patients, and future research directions. Abstract P0855. gammadelta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. Breast cancer survivor studies showed a clear positive association between obesity and mortality in estrogen receptor-positive breast cancer patients but not in other subtypes such as triple-negative and human epidermal growth factor receptor 2–positive types (79, 80). The lack of concern for skin cancer looks like this: More than two-thirds of the respondents (69%) have at least one possible risk factor -- … 2015;23(12):2485-90. Thymic fatness and approaches to enhance thymopoietic fitness in aging. BACKGROUND Obesity, defined by body mass index (BMI), appears to have a paradoxical protective effect in several chronic diseases. 2018;26(4):629-30. 1. Immunotherapy implications in obese cancer patients. Fausto Petrelli1, Alessio Cortellini2, Alice Indini3, Gianluca Tomasello4, Michele Ghidini3, Olga Nigro5, Massimiliano Salati6, Lorenzo Dottorini7, Alessandro Iaculli7, Antonio Varricchio8, Valentina Rampulla8, Sandro Barni1, Mary Cabiddu1, Antonio Bossi9, Antonio In early stage disease, clinical trials report pathological complete response rates of 20–60% using combinatorial and/or concurrent treatments of PD-L1 inhibition with chemotherapy (11). doi: 10.1038/nrclinonc.2016.217, 72. Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, et al. Obesity paradox in cancer: new insights provided by body composition1–3 Maria Cristina Gonzalez, Carla A Pastore, Silvana P Orlandi, and Steven B Heymsfield ABSTRACT Weight loss and cachexia are well-defined morbidity and Background: Obesity, defined by body mass index (BMI), appears mortality risk factors in cancer patients (2, 4). Due to the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor (Her2), until recently, cytotoxic chemotherapy was the only approved systemic treatment option for TNBC. Immunol Res. When the analysis is restricted to cancer patients (i.e., conditioned on cancer), obese cancer patients are less likely to be smokers, whereas nonobese cancer patients are more likely to be smokers. "This obesity paradox has been seen in some other cancers, possibly due to the relationship between tissue fat and cancer genomes, and more research is needed in this area. In venous thromboembolism (VTE), evidence for an obesity paradox has been established in large patient cohorts. Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, et al. Blood. J Exp Med. Cancer top. Int J Cancer. Fausto Petrelli1, Alessio Cortellini2, Alice Indini3, Gianluca Tomasello4, Michele Ghidini3, Olga Nigro5, Massimiliano Salati6, Lorenzo Dottorini7, Alessandro Iaculli7, Antonio Varricchio8, Valentina Rampulla8, Sandro Barni1, Mary Cabiddu1, Antonio Bossi9, Antonio PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. Jim Stallard Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. (2015) 10:e0120918. (2013) 110:15919–24. Cell Immunol. This apparent obesity paradox may be largely explained by methodological limitations including reverse causation, selection bias, confounding, and reliance of BMI as a measure of adiposity in cancer patients. A typical adjustment for smoking status or pack-years of smoking is not enough to avoid residual confounding (19). Presented at: EAU 2021, held July 8-12, 2021. Cell Res. Nat Cell Biol. When a specific body composition such as visceral fat mass and muscle mass was examined in relation to cancer survival, most studies found poor cancer survival with higher visceral fat mass and/or reduced muscle mass (50–57). “Why are these immune cells going only to the fat and not getting to the tumor?”. Colditz, Writing, review, and/or revision of the manuscript: Y. Prostate Cancer Prostatic Dis. The Obesity Paradox: A Misleading Term That Should Be Abandoned. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive. doi: 10.1194/jlr.M500294-JLR200, 74. doi: 10.1038/cr.2012.178, 89. Based on our current knowledge, we can foresee several challenges and opportunities for the clinical management of cancer immunotherapy in obese patients. Blood. Download : Download high-res image (1012KB) Download : Download full-size image; Fig. The major objectives of this book were to present the most recent advances in our understanding of how tumor cells metastasize to secondary sites by the leading experts in the biology of tumor invasion and metastasis. Nature. Cancer Sci. doi: 10.1200/JCO.2018.36.15_suppl.e15050, 98. According to the Million Women Study, obesity contributes to 5% of all cancers in postmenopausal women (18). Found insideIn How Not to Die, Dr. Michael Greger, the internationally-renowned nutrition expert, physician, and founder of NutritionFacts.org, examines the fifteen top causes of premature death in America-heart disease, various cancers, diabetes, ... (2017) 117:1583–91. These findings support a potential obesity paradox in bladder cancer. Costanzo AE, Taylor KR, Dutt S, Han PP, Fujioka K, Jameson JM. (2014) 192:623–9. Therefore, this review summarizes a number of hypothesized methodologic explanations that may have caused spurious associations that led to the obesity paradox in some cancers. Found insideIn a brief, clear and easily accessible way, this summary illustrates the dynamics of the obesity epidemic and its impact on public health throughout the WHO European Region, particularly in eastern countries. 2013;226(1):186-192. In 2014, a team led by epidemiologist Helena Furberg and urologic oncology surgeon Ari Hakimi found that tumors in obese people may grow slower because they have less activity in a cancer-promoting gene. MSK researchers have discovered that fat surrounding kidney tumors may play a key role in the effectiveness of kidney cancer treatments. The lack of tumor response in obese mice was accompanied by an increase in regulatory DCs and a decrease in tumor infiltration of IFN-γ-producing CD8+ T cells. More specifically, CD8+ T cells, IFN-γ producing Th1 cells, neutrophils, B cells, and NK cells can stimulate M1 macrophage polarization, infiltration, and activation (76). Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, Seewaldt V, et al. Online ahead of print.ABSTRACTOBJECTIVE: To test whether body mass index (BMI) (2017) 8:643. doi: 10.3389/fimmu.2017.00643, 46. Adapting to obesity with adipose tissue inflammation. In this respect, preclinical studies have demonstrated additional benefit from combining checkpoint blockade with strategies to intervene with TAM accumulation, polarization, and/or function (72). The costs of publication of this article were defrayed in part by the payment of page charges. Clin Cancer Res. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. doi: 10.1016/j.cellimm.2018.03.001, 77. Studies on premenopausal breast cancer risk show a degree of inconsistency with null or lower risk of ER+ breast cancer and higher risk of TNBC with obesity (19). Macrophage plasticity, polarization, and function in health and disease. (2017) 19:974–87. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with … Sun H, Zou J, Chen L, Zu X, Wen G, Zhong J. Triple-negative breast cancer and its association with obesity. Magnetic resonance imaging and CT can directly quantify adiposity in different compartments such as visceral adipose tissue, but they are expensive and not readily available in studies and clinics (85). "I read this book... it worked. Upregulation of TGF-β has been shown to impair CAR-T cell proliferation and activity, and to downregulate intracellular levels of perforin, GM-CSF, and IFN-γ (97). Obesity and cancer immunotherapy toxicity. Since immunotherapy is an emerging anti-cancer treatment strategy, it is pivotal to gain insight into possible deleterious effects of obesity on immunotherapy tolerance and response. Lynch LA, O'Connell JM, Kwasnik AK, Cawood TJ, O'Farrelly C, O'Shea DB. This plasticity could in part explain why γδ T cells have been associated with poor prognosis in breast cancer (39) and why the results from γδ T cell-based immunotherapy have been rather disappointing (38). "This obesity paradox has been seen in some other cancers, possibly due to the relationship between tissue fat and cancer genomes, and more research is needed in this area," said Dr. Nicola Fossati. On another note, similar to M2 macrophages, M2-like TAMs inhibit CD8+ signaling and function through the secretion of immunosuppressive molecules (IL-10, TGF-β, ARG-1, prostaglandins) (66). 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