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.
Highlights
Current progress in cancer immunology elucidates the importance of immune checkpoint regulation [1]
Through cancer treatment using HVJ-E+poly cytidylic acid (poly I):C, we conclude that tumor-associated neutrophils (TANs) are recruited by CXCL2 to exert anti-tumor activity in the tumor microenvironment (TME) in response to HVJ-E treatment
It has been posited that TME reconstruction induced by altering the pro-tumorigenic phenotype of TANs and tumor-associated macrophages (TAMs) to the anti-tumorigenic phenotype may be more effective for enhancing anti-tumor immunity, as suggested by TGF-β blockade therapy [20]
Summary
Current progress in cancer immunology elucidates the importance of immune checkpoint regulation [1]. Immuno-tolerance against cancers is achieved through the activation of immune checkpoint systems by cancer cells [2, 3]. A representative example is the expression of the PD-1 ligands, PD-L1 and L2, on the surface of cancer cells, which attenuates T cell function via PD-1 signal transduction to generate exhausted T cells [2, 3]. PD-1 ligands are expressed in both cancer cells and tumor-infiltrating immune cells, such as macrophages and dendritic cells [4, 5]. Cancers that express PD-L1 in immune cells are likely to be more aggressive than those exclusively expressing PD-L1 in cancer cells [5]. The immune cells are originally antitumorigenic, presenting tumor antigens and activating
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
