Virus stimulated neutrophils in the tumor microenvironment enhance T cell mediated anti tumor immunity
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 naive 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.
Oncotarget