The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy

Assumpção, José Antônio Fagundes; Pasquarelli-do-Nascimento, Gabriel; Duarte, Mariana Saldanha Viegas; Bonamino, Martín; Magalhães, Kelly Grace

doi:10.1186/s12929-022-00796-0

Cited by 36 publications

(47 citation statements)

References 442 publications

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“…Obesity and albumin have been recognized as essential parameters for evaluating the nutritional status of patients with cancer ( 43 ). At present, obesity is associated with inflammatory response and affects the efficiency and toxicity of chemotherapy and radiotherapy in patients with cancer ( 44 – 46 ). The inflammatory indexes in the peripheral blood, NLR, MLR, PLR, and SII have been used as markers of predicting efficacy and toxicity of NCRT in patients with LARC in our previous study ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of mesorectal package area in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy: A retrospective cohort study

Guan

Huang²,

Huang³

et al. 2022

Front. Oncol.

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BackgroundThe aim of this study is to explore the most effective inflammation, magnetic resonance imaging (MRI), and nutrition markers for survival and pathology complete response (pCR) in patients with locally advanced rectal cancer (LARC).MethodsA total of 278 patients with LARC undergoing neoadjuvant chemoradiotherapy (NCRT) and radical surgery from 2016 to 2019 were included. The X-tile method was used to select the optimal cutoff points for the mesorectal package area (MPA), advanced lung cancer inflammation index (ALI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) scores. Cox regression analysis was used to identify risk factors of disease-free survival (DFS). To discover pCR risk factors, logistic regression analysis was employed. A predictive nomogram for DFS was constructed.ResultsAccording to the least absolute shrinkage and selection operator analysis, the MPA was the only significant predictor for the DFS in patients with LARC. Kaplan-Meier (K-M) analysis demonstrated that groups with higher MPA, PNI, SII, NLR, MLR, and ALI score had improved DFS (all P < 0.05). Receiver operating characteristic (ROC) analysis revealed that the MPA and PNI could accurately predict the pCR in patients with LARC after NCRT. The MPA score and NLR score were found to be independent predictors of DFS after NCRT using Cox regression analysis. Logistical regression analysis demonstrated that the MPA score, PNI score, and pre-NCRT cN stage were all independent predictors of pCR in patients with LARC after NCRT. Recursive partitioning analysis and time-independent ROC curve analysis demonstrated that MPA score was the most important predictor of pCR and prognosis in patients with LARC after NCRT.ConclusionsMPA was identified as the most effective marker for MRI, and the prognostic value was further confirmed by time–ROC analysis. More intense adjuvant treatment could be considered for lower–MPA score patients with LARC after NCRT. Obesity in the pelvis encourages the understanding of the prognosis prediction of patients with LARC after NCRT.

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Section: Discussionmentioning

confidence: 99%

Prognostic value of mesorectal package area in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy: A retrospective cohort study

Guan

Huang²,

Huang³

et al. 2022

Front. Oncol.

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“…Obesity is a leading risk factor for progression and metastasis of many cancers 1,2 , yet can also promote improved survival for some cancers [3][4][5] and enhance responses to some immune checkpoint blockade therapies [6][7][8] . The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear.…”

Section: Discussionmentioning

confidence: 99%

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Bader

Wolf

Madden

et al. 2022

Preprint

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Obesity is a leading risk factor for progression and metastasis of many cancers, yet can also promote improved survival for some cancers and enhance responses to some immune checkpoint blockade therapies. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner. PD-1+ TAMs had increased mitochondrial respiration and expression of genes regulating oxidative phosphorylation, lipid uptake and cell cycle while PD-1- TAMs showed greater signatures of phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis and phagocytic capacity, and this was reversed with blocking PD-1 antibody. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

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“…This phenomenon is termed the “obesity paradox” and has been reported for different cancer types. Visceral adipose tissue is in fact considered an endocrine organ, responsible for secreting various factors which regulate innate and adaptive immunity, hematopoiesis, and angiogenesis ( 62 ).…”

Section: Flat Doses and Doses Based On Body Surface Area Hamper Perso...mentioning

confidence: 99%

Sex and Gender Differences in Anticancer Treatment Toxicity: A Call for Revisiting Drug Dosing in Oncology

2022

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The practice of oncology has dramatically changed in the last decade with the introduction of molecular tumor profiling into routine tumor diagnostics and the extraordinary progress in immunotherapies. However, there remains an unmet need to explore personalized dosing strategies that take into account the patient’s sex to optimize the balance between efficacy and toxicity for each individual patient. In this mini-review, we summarize the evidence on sex differences in toxicity of anticancer therapies and present data on dose reduction and dose discontinuation rates for selected chemotherapies and targeted therapies. Finally, we propose the investigation of body composition (specifically fat free muscle mass) as a viable approach for personalized treatment dosage.

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The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy

Cited by 36 publications

References 442 publications

Prognostic value of mesorectal package area in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy: A retrospective cohort study

Prognostic value of mesorectal package area in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy: A retrospective cohort study

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Sex and Gender Differences in Anticancer Treatment Toxicity: A Call for Revisiting Drug Dosing in Oncology

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