Enhanced Tumor Metastasis in Response to Blockade of the Chemokine Receptor CXCR6 Is Overcome by NKT Cell Activation

Abstract

Invariant NKT (iNKT) cells can induce potent antitumor responses in vivo. However, the mechanisms that regulate the effects of iNKT cells are unclear. The chemokine receptor CXCR6, and its ligand CXCL16, have been shown to play critical roles in iNKT cell homeostasis and activation. Thus we investigated the role of CXCR6 in protection against experimental metastasis of B16-F10 melanoma (B16) and Lewis lung carcinoma (LLC) cells to the liver and lungs. Wild-type and CXCR6−/− mice exhibited no differences in tumor cell metastasis to the lungs. However, metastasis of LLC and B16 tumor cells to the liver was enhanced in CXCR6−/− mice. Liver metastasis was also increased in wild-type mice treated with a CXCL16 neutralizing Ab. As Ab treatments did not alter iNKT cell numbers, this implicates a direct role for CXCR6/CXCL16 in regulating antitumor immunity. Cytokine induction was significantly attenuated in CXCR6−/− mice upon systemic iNKT cell activation with the glycolipid Ags α-galactosylceramide (α-GalCer), α-C-GalCer (a Th1 polarizing derivative), or OCH (a Th2 polarizing derivative). Despite differences in the levels of cytokine production, liver and lung metastasis were inhibited significantly in both wild-type and CXCR6−/− mice treated with glycolipids. Single doses of α-GalCer, α-C-GalCer, or OCH were sufficient to prevent liver metastasis and subsequent doses failed to elicit optimal cytokine responses. Our findings implicate a role for CXCR6 in natural immunosurveillance against liver metastasis. However, CXCR6 deficiency could be overcome by systemic iNKT cell activation, demonstrating that even suboptimal iNKT cell activation can protect against metastasis.

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…7,15,16,21,30,31 Although clinical trials examining NKT cell activation therapies in patients with advanced/recurrent disease have reported few cases of objective tumor regression, tumors tended to remain stable without the appearance of new metastatic foci. 15,[17][18][19][20]35 This suggests that NKT cell activation therapy might be more effective at targeting metastatic disease than primary tumors.…”

“…While Th1 skewing is important for tumor control in mouse models, 31,33,34 and elevated IFNg production is associated with prolonged survival in clinical trials, 20,35 we previously found that OCH treatment effectively controlled metastasis of B16 melanoma and Lewis lung carcinoma cells to the liver in C57BL/6 mice. 7 It is likely that the ratio of Th1:Th2 cytokines ultimately impacts tumor control, and differences in immune skewing between BALB/c and C57BL/6 mice could influence the effect of OCH. We focused on a-GalCer in this study because it has been used extensively in human clinical trials where it has been shown to be safe and well tolerated.…”

“…7,16,30 We investigated whether a-GalCer, a Th1-polarizing analog (a-C-GalCer), 31 or a Th2 polarizing analog (OCH) 32 could protect mice from 4T1 breast cancer metastasis. In our postsurgical breast cancer model (Fig.…”

“…4 Following activation, NKT cells can produce a wide array of immunoregulatory cytokines, including interferon-g (IFNg), tumor necrosis factor, interleukin-2 (IL-2), IL-4, IL-10, IL-13, IL-17, IL-21, and granulocyte-macrophage colony-stimulating factor (GM-CSF). [5][6][7] Rapid cytokine production enables NKT cells to influence downstream immune responses, making them a promising therapeutic target for immune modulation therapy.…”

Type I natural killer T cells: naturally born for fighting

“…NKT cells directly eradicate target cells through cell death inducing ligands FasL and TNF-related apoptotic induced ligand (TRAIL) [69] . The recruitment of leukocytes into tissues is dependent on a series of adhesive and activation steps mediated by adhesion molecules and interaction of chemokine and chemokine receptors, which restrict their tissue and microenvironmental distribution [70][71][72] . In this regard, NKT cells resemble effector T cells because CD4 + , CD8 + , and DN subsets uniformly express non-lymphoidtissue-homing chemokine receptors, such as CCR2, CCR5, and CXCR3 [70] .…”