BackgroundPancreatic 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.MethodsBxPC-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. χ2test, two-tailed unpaired t-test or Kaplan-Meier survival analysis was used to calculate p values.ResultsPD1/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.ConclusionOur 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.
Aim. To evaluate the possible association between the vitamin D receptor (VDR), single-nucleotide polymorphisms (SNPs), and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Method. 968 chronic HBV infection patients were enrolled, of which 436 patients were diagnosed HCC patients, and 532 were non-HCC patients. The clinicopathological characteristics of HCC were evaluated. The genotypes of VDR gene at FokI, BsmI, ApaI, and TaqI were determined. Results. The genotype frequencies of VDR FokI C>T polymorphism were significantly different between HCC and non-HCC groups. HCC patients had a higher prevalence of FokI TT genotype than non-HCC subjects. With FokI CC as reference, the TT carriage had a significantly higher risk for development of HCC after adjustments with age, sex, HBV infection time, α-fetoprotein, smoking status, and alcohol intake. In addition, we also found that the TT genotype carriage of FokI polymorphisms were associated with advanced tumor stage, presence of cirrhosis, and lymph node metastasis. The SNP at BsmI, ApaI, and TaqI did not show positive association with the risk and clinicopathological features of HCC. Conclusion. The FokI C>T polymorphisms may be used as a molecular marker to predict the risk and to evaluate the disease severity of HCC in those infected with HBV.
Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.