Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer
Authors: Guoliang Cao
Xiaodong Xu
Guoping Ding
Qiang Wei
Qiang Yan
Liping Cao
Neng Lou
Huilian Huang
Lifeng Huang
Mingjie Zhang
Xu Sun
Tao Shen
Journal: Journal for ImmunoTherapy of Cancer (2020)
Discipline: IMMUNOLOGY
Keywords: CXCL8; CXCR2; cancer immunotherapy; interferon-gamma (IFN-γ); macrophages
Affiliations: Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China   ., Key Laboratory of Biomedicine and Health, Hangzhou Normal University Hangzhou School of Medicine, Hangzhou, China., Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China., Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, China., Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China., Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China   .

Abstract:  Background: Pancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression. Programmed death 1 (PD1) blockade therapy is a promising treatment for patients with PC, but is yet to achieve significant clinical effects so far. Interferon gamma (IFN-γ) is a soluble dimeric cytokine that is closely associated with tumor immune surveillance and cytotoxicity. IFN-γ suppresses a variety of tumor-derived cytokines in PC, such as CXCL8. In the present study, we investigated the therapeutic efficacy of combined anti-PD1 and IFN-γ treatment in PC. Methods: BxPC-3 and Panc-1 human PC cell lines were used to construct a murine PC model. Blood samples (n=44) and surgical resection specimens (n=36) from human patients with PC were also collected. χ2 test, two-tailed unpaired t-test or Kaplan-Meier survival analysis was used to calculate p values. Results: PD1/PD-L1 signaling was overexpressed in PC tumor-bearing mice. Anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 treatment showed limited benefit. Murine PC model had a preferential expansion of CXCR2+CD68+ macrophages, and these cells showed an immunosuppressive nature (M2 polarization). PC tumors overexpressed CXCL8 and tumor-derived CXCL8 deficiency prohibited the trafficking of CXCR2+CD68+ macrophages. IFN-γ suppressed the expression of tumor-derived CXCL8, and combined with IFN-γ treatment, delayed anti-PD1 treatment showed significant antitumor effects. Thus, we conclude that murine CXCR2+CD68+ macrophages traffic to PC tumors by tumor-derived CXCL8 and mediate local immunosuppression, which limits the efficacy of PD1 blockade therapy. IFN-γ suppresses tumor-derived CXCL8 and inhibits the tumor trafficking of CXCR2+CD68+ macrophages by blocking the CXCL8-CXCR2 axis to enhance anti-PD1 efficacy. Human PC also produces high levels of CXCL8. Patients with PC present elevated CXCR2 expression on peripheral and tumor-infiltrating CD68+ macrophages, which are associated with advanced tumor stage and poor prognosis. Conclusion: Our findings suggest that IFN-γ is a translatable, therapeutic option to improve the efficacy of PD1 blockade therapy by preventing trafficking of CXCR2+CD68+ macrophages via blocking the CXCL8-CXCR2 axis. 

Retracted: No

PubPeer comments:
 Figure 2C appears to have some repeated features, shown in red and green across several images. However, there are also some differences between these images shown with arrows. One image needs to be flipped in order to compare. See below. *** Closeup ![file] *** Original positioning ![file] *** Full figure ![file] , 
 Dear editor We are really sorry for our mistake. We want to change the figure 3C. Because the revised figure 3 was greater than 1MB, this figure was up-loaded via email as an attachment. We are very sorry for the inconvenience. Thank you very much for your attention and consideration. Yours sincerely, Jian Song , 
 #2 Thank you for your reply. You may already understand this, but this is a post publication peer review website, similar to a journal club. If you wish to contact the editor of the journal, you will need to contact them directly. If you wish to provide a copy of your replacement image to readers here, you may be able to do so by uploading the image at: https: m.imgur.com and then provide a link to that file here. Emails sent to PubPeer, the host of this site, are generally not posted by the moderators. Lastly, I would appreciate an explanation of how the images in the original figure were generated. The images are not identical, but have several common features. This is puzzling. , 
 Fig 2B - two EdU panels have been repeated by mistake. This mix-up is presumably why the red channel in each Merged panel does not match the EdU panel. ![file] , 
 #4 Fig 2B ![](http: i.imgur.com 3yGvOut.jpg) , 
 2020 retraction. https: portlandpress.com bioscirep article 40 6 BSR-20194427_RET 225493 Retraction-Silencing-of-LncRNA-PVT1-inhibits-the The article u201cSilencing of LncRNA PVT1 inhibits the proliferation, migration and fibrosis of high glucose-induced mouse mesangial cells via targeting microRNA-93-5pu201d (Bioscience Reports (2020) 40(5), DOI: 10.1042 BSR20194427) is being retracted at the request of the Editor-in-Chief and the Editorial Board following receipt of a notification from a reader, alerting the Editorial Board to manipulation in Figure 3C, as well as duplicated images in Figures 2B, 4B, 7B and 7D. The authors have been contacted in regard to the retraction, and disagree with the Journal s decision to retract the article; however, the Editorial Board stand by the decision to retract given the concerns with the figures. , 
 #6 Unfortunately, I believe the journal made an error in the retraction statement. The manipulation reported in #1 is for 2C, not 3C (as the authors reply in #2 misstated). ,