Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy

Abstract

It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1β. PSCs further secrete IL-1β, and inactivation of PSCs reduces IL-1β expression and TAN recruitment. Furthermore, depletion of TANs, IL-1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

“…For example, adipocyte-secreted vascular endothelial growth factor (VEGF)-A and interleukin (IL)-1β promote tumor angiogenesis and recruitment of immunosuppressive neutrophils to the tumor microenvironment, respectively. 37,38 Given the impact of adiposity on breast cancer development and progression and the complexity of the tumor microenvironment, it is important to understand the tumor-adipose network better.…”

Adipocytes and Neutrophils Give a Helping Hand to Pancreatic Cancers

“…Neutrophil depletion, IL1β inhibition, and AT1 blockade also increased CD8 + T cells and reduced T regulatory lymphocytes in tumors from obese but not lean mice, suggesting a role for TANs in regulating the immune contexture of PDAC. In line with the preclinical data, a study in 309 patients with PDAC confi rmed that adjuvant chemotherapy following surgical resection resulted in a better overall survival in normal-weight patients compared with obese patients ( 3 ).…”

“…Moreover, pancreatic steatosis is associated with heightened PDAC risk and plays a negative prognostic role in patients with PDAC ( 1,2 ). Starting from previously published data showing that obesity increases the proinfl ammatory cytokine IL1β and fuels an infl ammatory milieu associated with accelerated tumor growth and metastasis formation, Incio and colleagues show that obesity shapes a distinctive PDAC microenvironment characterized by adipocyte accumulation and hypertrophy, local cross-talk between tumor-associated neutrophils (TAN) and PSCs, and the production of proinfl ammatory and profi brotic factors, which in turn favor tumor progression and severely limit the delivery of chemotherapeutic drugs ( 3 ). Some crucial molecular events support the intricate cell network that is established by diet-induced obesity.…”

Pancreatic Cancer and Obesity: Some Molecular Perspectives

“…Desmoplasia, a result of the proliferation of cancer associated fibroblasts and increased deposition of extracellular matrix, leads to reduced elasticity of tumor tissue with a concomitant increase in tumor interstitial fluid pressure, which results in a decreased rate of perfusion of therapeutic agents and consequently decreased efficacy [12]. Studies have shown that in obesity, the crosstalk between adipocytes, tumor associated neutrophils and pancreatic stellate cells promotes desmoplasia in mouse models of PC, and leads to accelerated tumor growth [13].…”