Laura Raccosta

Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol-CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol-CXCR2 axis and a possible target for cancer therapy.

Significance Oxysterols promote tumor growth directly or through the dampening of tumor-infiltrating immune cells. Whether oxysterols contribute to pancreatic neuroendocrine tumor (pNET) development and how they are generated within the pNET microenvironment are currently unknown. Here, we show that the 24S-hydroxycholesterol (24S-HC) oxysterol-generating enzyme Cyp46a1 is overexpressed during the angiogenic switch in rat insulin promoter 1–T-antigen 2 (RIP1-Tag2) pNET formation. Moreover, we report that Cyp46a1 overexpression requires hypoxia inducible factor-1a (HIF-1α). Importantly, we show that pharmacologic blockade and genetic inactivation of 24S-HC delays angiogenic switch and therefore tumor formation in RIP1-Tag2. Overexpression of Cyp46a1 transcripts in some human pNET samples suggests that targeting this axis in patients affected by pancreatic neuroendocrine tumors may be an effective therapeutic strategy.

Dendritic cell (DC) targeting in vivo has recently been shown to confer strong and protective cytotoxic T lymphocyte (CTL)-based immunity in tumor murine models. Our group has recently demonstrated in preclinical models that the infusion of genetically modified lymphocytes (GMLs) expressing the self/tumor antigen TRP-2 is able to elicit functional TRP-2-specific effectors with antitumor activity by targeting DCs in vivo. Here we have analyzed vaccine- and tumor-specific immune responses of 10 melanoma patients treated with autologous GMLs expressing the cancer germline gene MAGE-A3. Three of 10 patients treated with MAGE-A3-GML showed an increase of circulating anti-MAGE-A3 T cells, and developed skin delayed-type hypersensitivity to MAGE-A3. Interestingly, in 2 of these patients, with progressive and measurable tumors at study entry, anti-MAGE-A3 T cells were detected not only in the blood but also within tumors resected after vaccination. These results demonstrate that the infusion of MAGE-A3-GML elicits antitumor T cells, which are capable of trafficking to inflamed tissues and of infiltrating tumors. Clinical studies on a larger group of patients are needed to evaluate the clinical efficacy of such a strategy.