PD-1 blockade therapy in renal cell carcinoma: Current studies and future promises

Massari, Francesco; Santoni, Matteo; Ciccarese, Chiara; Santini, Daniele; Alfieri, Salvatore; Martignoni, Guido; Brunelli, Matteo; Piva, Francesco; Berardi, Rossana; Montironi, Rodolfo; Porta, Camillo; Cascinu, Stefano; Tortora, Giampaolo

doi:10.1016/j.ctrv.2014.12.013

Cited by 165 publications

(116 citation statements)

References 68 publications

(81 reference statements)

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“…Several biomarkers and or immune-molecular portraits have been studied in the attempt to identify responder patients, such as those who most likely will benefit from anti-PD-L1 treatment (31). One of the mechanism of tumor silencing of immunity involves DCs, the main orchestrators of the immune system (32,33).…”

Section: Immune Profile Of Mrcc Patients During Tki Treatmentmentioning

confidence: 99%

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Zizzari

Napoletano

Botticelli

et al. 2018

Cancer Immunology Research

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Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/b-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4 þ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711-22. Ó2018 AACR.

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Section: Immune Profile Of Mrcc Patients During Tki Treatmentmentioning

confidence: 99%

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Zizzari

Napoletano

Botticelli

et al. 2018

Cancer Immunology Research

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“…Recently, aberrant PD-L1 and PD-L2 expression by cancer cells has been reported in many human malignancies (17)(18)(19). A series of clinical trials concerning the systemic administration of therapeutic antibodies for blocking PD-1 or PD-L1 have shown a promising clinical effect in various tumors (20,21).…”

Section: Introductionmentioning

confidence: 99%

Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

Leng

Qin

et al. 2015

Oncology Reports

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Abstract. The programmed death-1 (PD-1)/programmed death-ligands (PD-Ls) signal pathway has been implicated as a potential immune escape mechanism in several human cancers. However, the studies of PD-1/PD-Ls pathway in esophageal squamous cell carcinoma (ECSS) are not yet sufficient. The current study investigated the expression of PD-L1, PD-L2 and PD-1 in ESCC tissues. The correlations between the expression of these proteins and clinical histopathological parameters were analyzed. Then the stable transfected Ec109 cell lines overexpressing PD-L1/PD-L2 were established by plasmid transfection successfully. Ec109 and CD8 + T cells were co-cultured to analyze the effects of PD-1/PD-Ls signal pathway on the function of CD8 + T cells including proliferation, apoptosis and interferon-γ production. We found that PD-L1-positive patients had significantly poorer prognosis than the negative patients, while their prognosis was not related to PD-L2 expression. The count of PD-1 + TILs (tumor-infiltrating lymphocytes) was negatively correlated with both PD-L1 and PD-L2 expression. In functional studies, we found that PD-1/PD-Ls signal pathway was able to downregulate the function of CD8 + T lymphocyte and its function could be restored by blocking the signal pathway. This indicates that PD-1/PD-Ls may prevent effective antitumor immunity, which provides important evidence to delineate the cellular immune deficiency mechanism in ESCC. Therefore, PD-1/PD-Ls are predicted to become novel targets for ESCC immunotherapy.

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“…CTLA-4 and PD-1 are immune checkpoint molecules that downregulate T-cell activation pathways, thereby hindering the immune response to cancer. Immune checkpoint inhibition, specifically by CTLA-4 and PD-1 blockade, has been implemented in cancers such as melanoma [86], renal cell carcinoma [87] and non-small-cell lung cancer [88], with significant clinical efficacy and survival benefit. In a Phase III study of 676 patients with unresectable stage III or IV melanoma, ipilimumab revealed improved overall median survival in patients with advanced melanoma (10 vs 6.4 months in controls; p < 0.001) [85].…”

Section: Gbm Immunotherapy and Precision Medicinementioning

confidence: 99%

Immunotherapy in glioblastoma: emerging options in precision medicine

2016

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Immunotherapy for glioblastoma (GBM) provides a unique opportunity for targeted therapies for each patient, addressing individual variability in genes, tumor biomarkers and clinical profile. As immunotherapy has the potential to specifically target tumor cells with minimal risk to normal tissue, several immunotherapeutic strategies are currently being evaluated in clinical trials in GBM. With the Precision Medicine Initiative being announced in the President's State of the Union Address in 2016, GBM immunotherapy provides a useful platform for changing the landscape in treating patients with difficult disease.

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PD-1 blockade therapy in renal cell carcinoma: Current studies and future promises

Cited by 165 publications

References 68 publications

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

Immunotherapy in glioblastoma: emerging options in precision medicine

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