Research Papers:

Virus-stimulated neutrophils in the tumor microenvironment enhance T cell-mediated anti-tumor immunity

Chin Yang Chang _, Jiayu A. Tai, Sumin Li, Tomoyuki Nishikawa and Yasufumi Kaneda

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Oncotarget. 2016; 7:42195-42207. https://doi.org/10.18632/oncotarget.9743

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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: kaneday@gts.med.osaka-u.ac.jp

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


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.

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