Effects of Hyperthermia and Hyperthermic Intraperitoneal Chemoperfusion on the Peritoneal and Tumor Immune Contexture.

Hyperthermia combined with intraperitoneal (IP) drug delivery is increasingly used in the treatment of peritoneal metastases (PM). Hyperthermia enhances tumor perfusion and increases drug penetration after IP delivery. The peritoneum is increasingly recognized as an immune-privileged organ with its own distinct immune microenvironment. Here, we review the immune landscape of the healthy peritoneal cavity and immune contexture of peritoneal metastases. Next, we review the potential benefits and unwanted tumor-promoting effects of hyperthermia and the associated heat shock response on the tumor immune microenvironment. We highlight the potential modulating effect of hyperthermia on the biomechanical properties of tumor tissue and the consequences for immune cell infiltration. Data from translational and clinical studies are reviewed. We conclude that (mild) hyperthermia and HIPEC have the potential to enhance antitumor immunity, but detailed further studies are required to distinguish beneficial from tumor-promoting effects.

The tumor immune microenvironment in peritoneal carcinomatosis.

One in four patients with colorectal cancer, 40% of gastric cancer patients, and 60% of ovarian cancer patients will develop peritoneal metastases (PM) in the course of their disease. The outcome of patients with widespread PM remains poor with currently available treatments. Despite the relatively common occurrence of PM, little is known on the pathophysiology that drives the peritoneal metastatic cascade. It is increasingly recognized that the stromal components of the peritoneal microenvironment play an essential role in tumor progression. However, little is known about the specific interactions and components of the peritoneal tumor microenvironment, particularly with respect the immune cell population. We summarize the current knowledge of the tumor immune microenvironment (TIME) in peritoneal metastases originating from the three most common origins: ovarian, gastric, and colorectal cancer. Clearly, the TIME is highly heterogeneous and its composition and functional activity differ according to tumor type and, within the same patient, according to anatomical location. The TIME in PM remains to be explored in detail, and further elucidation of their immune contexture may allow biology driven design of novel immune modulating or immune targeting therapies.

Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis.

Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.