CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

Correction to: CXCL9 secreted by tumor-associated dendritic cells up-regulates PD-L1 expression in bladder cancer cells by activating the CXCR3 signaling

An amendment to this paper has been published and can be accessed via the original article.

IP-10 and CXCR3 signaling inhibit Zika virus replication in human prostate cells

Our previous studies have shown that Zika virus (ZIKV) replicates in human prostate cells, suggesting that the prostate may serve as a long-term reservoir for virus transmission. Here, we demonstrated that the innate immune responses generated to three distinct ZIKV strains (all isolated from human serum) were significantly different and dependent on their passage history (in mosquito, monkey, or human cells). In addition, some of these phenotypic differences were reduced by a single additional cell culture passage, suggesting that viruses that have been passaged more than 3 times from the patient sample will no longer reflect natural phenotypes. Two of the ZIKV strains analyzed induced high levels of the IP-10 chemokine and IFNγ in human prostate epithelial and stromal mesenchymal stem cells. To further understand the importance of these innate responses on ZIKV replication, we measured the effects of IP-10 and its downstream receptor, CXCR3, on RNA and virus production in prostate cells. Treatment with IP-10, CXCR3 agonist, or CXCR3 antagonist significantly altered ZIKV viral gene expression, depending on their passage in cells of relevant hosts (mosquito or human). We detected differences in gene expression of two primary CXCR3 isoforms (CXCR3-A and CXCR3-B) on the two cell types, possibly explaining differences in viral output. Lastly, we examined the effects of IP-10, agonist, or antagonist on cell death and proliferation under physiologically relevant infection rates, and detected no significant differences. Although we did not measure protein expression directly, our results indicate that CXCR3 signaling may be a target for therapeutics, to ultimately stop sexual transmission of this virus.

Sensitization of immunotherapeutic efficiency in HCC by polyinosinic-polycytidylic acid-triggered CXCL10 secretion in liver sinusoidal endothelial cells.

126 Background: Nowadays, the efficiency of immune checkpoint blockades (ICBs) in the treatment of advanced hepatocellular carcinoma (HCC) was low. The previous study we published in Hepatology demonstrated that polyinosinic-polycytidylic acid (PolyIC), a TLR3 agonist, could trigger the accumulation, proliferation and activation of CTLs, which contributes to the enhanced anti-tumor efficiency of PD-L1 Ab in HCC. However, the mechanism remains unclear. Methods: The mouse HCC model was established by hydrodynamic transfection of combinational c-Myc/N-Ras oncogenes. PolyIC, CTLA-4 Ab, PD-L1 Ab, CD8 Ab and CXCR3 Ab were all intraperitoneal injected. Mice liver non-parenchymal cells (NPCs) were isolated after liver perfusion and multistep centrifugation. The proliferation, activation and cytotoxic function of CTLs were assessed by flow cytometry. Liver sinusoidal endothelial cells (LSECs) were isolated by magnetic cell sorting. Expressions of TLR3 and CXCL10 were quantitatively analyzed by qRT-PCR and ELISA. LSECs were cultured in vitro by using DMEM medium. Results: Combination of polyIC and PD-L1 Ab (or CTLA-4 Ab) had a synergistic anti-tumor effect on the treatment of mouse HCC. PolyIC induced the accumulation, proliferation, activation and cytotoxic function of CTLs in liver, which were further enhanced when combined ICBs. And CTLs depletion by CD8 Ab attenuated the synergistic anti-tumor effect of polyIC when combined with ICBs. TLR3 expression was much higher in NPCs than other cells in liver, especially in LSECs. Also, polyIC dramatically induced the expressions of CXCL10 in LSECs both in vivo and in vitro. And in vitro, after treated by polyIC, the CXCL10 expression in the medium and cells were all elevated. What’s more, CXCL10/CXCR3 signaling blockade by CXCR3 Ab attenuated the combinational effects of polyIC and ICBs. Meanwhile, after CXCL10/CXCR3 signaling blockade, the accumulation, proliferation and activation of CTLs were all inhibited. Conclusions: PolyIC specifically targets LSECs to induce CXCL10 expression and secretion, which contributes to the CTLs transformation and enhanced efficiency of ICBs in the treatment of HCC.