Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells
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Kim C. Ohaegbulam1, Weifeng Liu2, Hyungjun Jeon1, Steven C. Almo2,3 and Xingxing Zang1,4,5
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
2Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
3Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA
4Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
5Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA
Xingxing Zang, email: [email protected]
Keywords: B7x, immune checkpoint, pulmonary metastases, CD8 T cells, innate cells
Received: July 12, 2017 Accepted: August 29, 2017 Published: September 20, 2017
B7x (B7-H4 or B7S1) is a coinhibitory member of the B7 immune checkpoint ligand family that regulates immune function following ligation with its unknown cognate receptors. B7x has limited expression on normal tissues, but is up-regulated on solid human tumors to inhibit anti-tumor immunity and associates with poor clinical prognosis. We assessed the contribution of cytokine stimuli to induce surface B7x expression on cancer cells and the role of tumor-expressed B7x in a murine pulmonary metastasis model, and finally evaluated the potential interaction between B7x and Neuropilin-1, a suggested potential cognate receptor. We showed that pro-inflammatory and anti-inflammatory cytokines IFNγ, TNFα, and IL-10 did not induce expression of B7x on human or murine cancer cells. Following i.v. injection of CT26, a murine colon cancer cell line in the BALB/c background, we observed a significant increase in tumor burden in the lung of B7x-expressing CT26 mice compared to B7x-negative parental CT26 control mice. This was marked by a significant increase in M2 tumor associated macrophages and antigen-specific CD8 T cell exhaustion. Finally, we found through multiple systems that there was no evidence for B7x and Neuropilin-1 direct interaction. Thus, the B7x pathway has an essential role in modulating the innate and adaptive immune cell infiltrate in the tumor microenvironment with its currently unknown cognate receptor(s).
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