Serum levels of soluble programmed cell death ligand 1 as a prognostic factor on the first-line treatment of metastatic or recurrent gastric cancer

Takahashi, Naoki; Iwasa, Satoru; Sasaki, Yo; Shoji, Hirokazu; Honma, Yoshitaka; Takashima, Atsuo; Okita, Natsuko; Kato, Ken; Hamaguchi, Tetsuya; Yamada, Yasuhide

doi:10.1007/s00432-016-2184-6

Cited by 75 publications

(85 citation statements)

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“…An increasing number of studies have reported that sPD-1 and sPD-L1 might play crucial roles in the prediction of treatment responses and prognosis in cancer patients [19–21]. However, the regulation, source and prognostic value of sPD-1/sPD-L1, as well as their association with clinicopathological factors in HCC, remain matters of debate.…”

Section: Discussionmentioning

confidence: 99%

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma

Chang

Huang

Wei

et al. 2018

Cancer Immunol Immunother

105

104

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BackgroundBlocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients.MethodsThis study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs.ResultsThe best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14–5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01–3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14–0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30–0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4+ TILs and CD8+ TILs were determined.ConclusionsOur findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2271-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma

Chang

Huang

Wei

et al. 2018

Cancer Immunol Immunother

105

104

View full text Add to dashboard Cite

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“…In this regard, future studies should examine if PD-L1 blockade in vivo , with or without IL-10(R) blockade, results in similar therapeutic efficacy in ovarian cancer as seen with the PD-1 blockade. Lastly, another potentially important finding is that IL-10 activated release of soluble PD-L1 (sPD-L1), a form of PD-L1 which induces apoptosis of T cells and has been repeatedly shown to be associated with poor outcome in patients with advanced cancers (41–45). …”

Section: Discussionmentioning

confidence: 99%

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

et al. 2017

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Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

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“…In other cancer entities, different approaches to determine prognostic cut-off values have been used: median sPD-L1 serum level in the analyzed cancer patient cohort, sPD-L1 serum levels in a corresponding cohort of healthy individuals or receiver operating characteristic (ROC) curve models to define an ideal prognostic cut-off value. [14][15][16][17][18] In all aforementioned studies, the prognostic cut-off value was in the range of the 50th (i.e., median) and 75th percentile of the observed sPD-L1 levels in the whole analyzed patient cohort. When designing our study we therefore decided to use the median and the 75th percentile of sPD-1 and sPD-L1 levels observed in our study to define a cohort of patients with high versus low levels of the two molecules.…”

Section: Spd-1 and Spd-l1 Elisasmentioning

confidence: 99%

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

et al. 2017

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Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet.In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD-L1 levels might be caused by an inflammatory tumor typeindependent of tumoral PD-L1 expression.

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Serum levels of soluble programmed cell death ligand 1 as a prognostic factor on the first-line treatment of metastatic or recurrent gastric cancer

Abstract: High serum levels of sPD-L1 correlated with worse overall survival on the first-line chemotherapy in metastatic GC patients.

Cited by 75 publications

References 58 publications

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

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