Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status

Ashizawa, Tadashi; Iizuka, Akira; Maeda, Chie; Tanaka, Emiko; Kondou, Ryota; Miyata, Haruo; Sugino, Takashi; Kawata, Takuya; Deguchi, Shoichi; Mitsuya, Koichi; Hayashi, Nakamasa; Asai, Akira; Ito, Mamoru; Yamaguchi, Ken; Akiyama, Yasuto

doi:10.1016/j.imlet.2019.10.003

Cited by 26 publications

(19 citation statements)

References 37 publications

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“…Conversely, other studies have shown that inhibition of STAT3 results in up-regulation of anti-apoptotic genes in PDAC cell lines [259]. Furthermore, whilst STAT3 inhibition alone reduced PDAC xenograft tumour growth, when used in combination with anti-PD-1, the beneficial effects of STAT3 inhibition were negated [260]. These conflicting results may be explained by the differential expression of STAT3 at various disease stages, or the ability of STAT3 to drive distinct responses in different genetic backgrounds and at different stages of disease [243].…”

Section: Do Il-6 Family Cytokines Represent a New Therapeutic Opportumentioning

confidence: 88%

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

2020

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Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.

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Section: Do Il-6 Family Cytokines Represent a New Therapeutic Opportumentioning

confidence: 88%

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

2020

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“…Accordingly, activation of P2 × 7 receptor can also participate in tumorigenesis by activating different intracellular signals (such as NF-kB, ERK, AKT, and mTOR) (Qiu et al, 2014;Amoroso et al, 2015;Zhang et al, 2019a). STAT3 is an important signaling pathway in tumor development (Ashizawa et al, 2019). Studies have shown that TP53 missense mutation (mutp53) promotes the growth of colon cancer by driving Jak2/Stat3 signaling (Greten et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

Zhang

Luo

et al. 2020

Front. Cell Dev. Biol.

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The pathological mechanism of colon cancer is very complicated. Therefore, exploring the molecular basis of the pathogenesis of colon cancer and finding a new therapeutic target has become an urgent problem to be solved in the treatment of colon cancer. ATP plays an important role in regulating the progression of tumor cells. P2 × 7 belongs to ATP ion channel receptor, which is involved in the progression of tumors. In this study, we explored the effect and molecular mechanism of ATP-mediated P2 × 7 receptor on the migration and metastasis of colon cancer cells. The results showed that ATP and BzATP significantly increased the inward current and intracellular calcium concentration of LOVO and SW480 cells, while the use of antagonists (A438079 and AZD9056) could reverse the above phenomenon. We found that ATP promoted the migration and invasion of LOVO and SW480 cells and is dose-dependent on ATP concentration (100–300 μM). Similarly, BzATP (10, 50, and 100 μM) also significantly promoted the migration and invasion of colon cancer cells in a concentration-dependent manner. While P2 × 7 receptor antagonists [A438079 (10 μM), AZD9056 (10 μM)] or P2 × 7 siRNA could significantly inhibit ATP-induced colon cancer cell migration and invasion. Moreover, in vivo experiments showed that ATP-induced activation of P2 × 7 receptor promoted the growth of tumors. Furthermore, P2 × 7 receptor activation down-regulated E-cadherin protein expression and up-regulated MMP-2 mRNA and concentration levels. Knocking down the expression of P2 × 7 receptor could significantly inhibit the increase in the expression of N-cadherin, Vimentin, Zeb1, and Snail induced by ATP. In addition, ATP time-dependently induced the activation of STAT3 via the P2 × 7 receptor, and the STAT3 pathway was required for the ATP-mediated invasion and migration. Our conclusion is that ATP-induced P2 × 7 receptor activation promotes the migration and invasion of colon cancer cells, possibly via the activation of STAT3 pathway. Therefore, the P2 × 7 receptor may be a potential target for the treatment of colon cancer.

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“…23 Based on these premises, one would expect that JAK2 inhibition might also reduce PDL1 expression, which has been proved in triple-negative breast cancer with 9p24.1 amplification. 24 However, inhibition of STAT3 pathway has been proven both to reduce the tumor infiltrating lymphocytes and response to checkpoint inhibitors, 25 and to interfere with the lymphocyte tumor-inhibitory Th1 pathway. 22 Since immunosurveillance is a major driver of survival in solid cancers, 26 we hypothesize that exposure to ruxolitinib in patients with SC might have favored cancer progression in a subgroup of SC patients.…”

Section: Discussionmentioning

confidence: 99%

Second cancers in MPN: Survival analysis from an international study

et al. 2019

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One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the

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Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status

Cited by 26 publications

References 37 publications

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

Activation of P2×7 Receptor Promotes the Invasion and Migration of Colon Cancer Cells via the STAT3 Signaling

Second cancers in MPN: Survival analysis from an international study

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