Research Papers:
Virus-stimulated neutrophils in the tumor microenvironment enhance T cell-mediated anti-tumor immunity
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 2219 views | HTML 6973 views | ?
Abstract
Chin Yang Chang1, Jiayu A. Tai1, Sumin Li1, Tomoyuki Nishikawa1, Yasufumi Kaneda1
1Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Correspondence to:
Yasufumi Kaneda, email: [email protected]
Keywords: HVJ-E, tumor associated neutrophils (TANs), anti-tumor immunity, tumor microenvironment (TME), cytotoxic T lymphocytes (CTLs)
Received: November 20, 2015 Accepted: May 22, 2016 Published: May 31, 2016
ABSTRACT
The tumor microenvironment (TME) fosters tumors by attenuating anti-tumor immunity, reinforcing tumor cell survival and increasing angiogenesis. Among the constituents of the TME, here, we focused on tumor-associated neutrophils (TANs). First, we found that the combination of poly I:C and inactivated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) synergistically suppressed tumor growth in the B16-F10 melanoma mouse model. In this model, poly I:C contributed to the recruitment of CD11b+Ly6G+ neutrophils to the TME, and co-injection of poly I:C and HVJ-E increased CD11b+Ly6G+FAS+ TAN in the TME. Depletion of neutrophils abolished the synergistic anti-tumor effect of HVJ-E and poly I:C in B16-F10 tumors. We revealed that C-X-C motif chemokine ligand 2 (CXCL2) is produced in the TME by poly I:C, but HVJ-E enhanced neutrophil infiltration of the TME does not occur. An anti-CXCL2 antibody inhibited the tumor suppression by HVJ-E+poly I:C. HVJ-E in combination with recombinant CXCL2 protein or CXCL2 pDNA suppressed mouse melanoma by increasing cytotoxic T lymphocyte activity against B16-F10 melanoma, which was abolished by an anti-Ly6G antibody. HVJ-E directly and indirectly increased FAS and ICAM-1 expression in cultured bone marrow-derived naïve neutrophils. Thus, HVJ-E activates anti-tumor immunity via anti-tumorigenic neutrophils in the TME. An HVJ-E vector containing the CXCL2 gene may be applicable as a novel cancer gene therapy strategy.

PII: 9743