Immunosuppressive CCR2+ cardiac macrophages mitigate myocardial injury in pancreatic cancer-associated cachexia

Cardiac wasting and injury are hallmarks of cancer cachexia, a metabolic syndrome characterized by reduced appetite and progressive loss of body weight in patients with cancer. However, the mechanisms underlying this cardiac pathology remain poorly understood. The heart is an immunologically complex organ, and cardiac myeloid cells have emerged as key regulators in various cardiomyopathies. Therefore, we investigated their contribution to cancer cachexia-induced cardiac wasting and injury. Using a murine model of pancreatic ductal adenocarcinoma (PDAC)-associated cachexia, we observed expansion of all cardiac macrophage subtypes and infiltration of neutrophils. Depletion of neutrophils had no impact on cardiac wasting and injury in tumor-bearing mice. In contrast, depletion of CCR2+ macrophages led to T cell expansion and activation within the heart, exacerbating myocardial inflammation and injury. These findings reveal a previously unrecognized protective immunosuppressive role for CCR2+ macrophages in PDAC cachexia. Finally, we identified reduced caloric intake as the major driver of cardiac wasting, highlighting a potential therapeutic avenue to preserve cardiac mass in patients with cancer cachexia.

心肌消耗与损伤是癌症恶病质的标志性病理特征。癌症恶病质是一类发生于癌症患者体内，以食欲减退、体重进行性丢失为特征的代谢综合征。然而，此类心脏病理改变的潜在分子机制仍未被充分阐明。心脏是免疫功能复杂的器官，而心脏髓系细胞已被证实是多种心肌疾病的关键调控因子。因此，本研究探讨了心脏髓系细胞在癌症恶病质诱导的心肌消耗与损伤中的作用。本研究采用胰腺导管腺癌（PDAC）相关性恶病质的小鼠模型，观察到所有心脏巨噬细胞亚型均发生增殖，同时伴随中性粒细胞浸润。清除中性粒细胞并不会对荷瘤小鼠的心肌消耗与损伤产生影响。与之相反，清除CCR2+巨噬细胞会促使心脏内T细胞增殖与活化，进而加重心肌炎症与损伤。上述研究结果揭示了CCR2+巨噬细胞在PDAC相关性恶病质中一种此前未被认知的保护性免疫抑制功能。本研究还证实，热量摄入减少是心肌消耗的主要驱动因素，为癌症恶病质患者维持心脏心肌质量提供了潜在的治疗途径。