Adipose PD-L1 Promotes Tumor Growth but Attenuates Obesity-Associated Inflammation
Open Access DepositedCostimulation signal plays a central role in regulating immune response and tissue homeostasis. Negative costimulation signal delivers suppressing effects on immune cell activation and function. As a salient example, PD-1/PD-L1 mediated signaling pathway dampens T cell effector, cytotoxic function and lead to T cell anergy. PD-1/PD-L1 signaling also inhibit pro-inflammatory polarization and phagocytosis of tissue resident macrophages to prevent excessive inflammation induced tissue damages. PD-L1 plays a critical role in mediating immune tolerance in a wide range of organs and biological processes including maternal-fetal immune tolerance. However, when hijacked by tumor cells, PD-L1 expressed by tumor or immune compartments within the tumor microenvironment can suppress immune mediated tumor cell killing, therefore favors tumor outgrowth. Although the current strategy targeting PD-1/PD-L1 has reshaped the paradigm of cancer treatment, the response rates in certain type of cancer are still unsatisfactory. Therefore, there is a pressing need to better understanding the complexity of tumor microenvironment and develop novel combination therapy to improve the patient outcome. Adipocytes, as one of the major cellular compartments of various kinds of tumor types, have been found to regulate tumor growth by distinct mechanisms. However, its role in regulating immune cells within the tumor microenvironment are less studied. In the current study, we found that mature adipocyte expresses high levels of PD-L1 that suppresses cytotoxic T cells function and therefore promotes aggressive tumor growth. Using both pharmacological inhibitor of adipogenesis and adipocyte-specific PD-L1 knockout mouse models, we were able to show that reducing PD-L1 can boost antitumor immune response and therefore delay tumor progression. Considering the central role of adipocyte in regulating metabolism, we also tested the role of adipocyte PD-L1 in regulating metabolism. We found that genetic ablation of PD-L1 in adipocytes accentuates high fat diet-induced obesity and associated metabolism disorder including glucose intolerance and insulin resistance, which was accompanied by exacerbated adipose tissue inflammation. To prove the clinical relevance, we extended our analysis to human samples and found that low adipocyte PD-L1 is associated with higher body mass index and increased chance of getting type 2 diabetes. Therefore, our finding informs potentially novel therapeutic strategy to boost anticancer immune response and also uncovers previously undiscovered role of adipocyte PD-L1 in regulating metabolism.
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