Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

Kleffel, Sonja; Posch, Christian; Barthel, Steven R.; Mueller, Hansgeorg; Schlapbach, Christoph; Guenova, Emmanuella; Elco, Christopher P.; Lee, Nayoung; Juneja, Vikram R.; Zhan, Qimin; Lian, Christine G.; Thomi, Rahel; Hoetzenecker, Wolfram; Cozzio, Antonio; Dummer, Reinhard; Mihm, Martín C.; Flaherty, Keith T.; Frank, Markus H.; Murphy, Gëorge F.; Sharpe, Arlene H.; Kupper, Thomas S.; Schatton, Tobias

doi:10.1016/j.cell.2015.08.052

Cited by 531 publications

(600 citation statements)

References 33 publications

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“…Preclinical and clinical correlative studies have demonstrated that PD-L1 and PD-1 pathway blockade is associated with B7 costimulation (11) and efficient T cell infiltration into tumor (12)(13)(14)(15). However, this pathway blockade may also directly target tumor cells and the therapeutic efficacy may not solely depend on the host immune system (16). As the antitumor effect of anti-PD-L1 is abolished in Rag1 -/-and NSG mice bearing multiple tumors, we conclude that the host adaptive immune system is essential for PD-L1 and PD-1 blockade-mediated antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Lin

Wei

Hurt³

et al. 2018

Journal of Clinical Investigation

471

373

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Section: Discussionmentioning

confidence: 99%

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Lin

Wei

Hurt³

et al. 2018

Journal of Clinical Investigation

471

373

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“…12 PD-1 expression has also been identified on a small fraction of melanoma cells, where its ligation promotes tumor growth. 13 The known ligands for PD-1 are the B7 family molecules PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), [14][15][16][17][18][19][20] which are cell membrane-bound glycoproteins that share 40% amino acid homology to each other. In normal human tissues, PD-L1 is expressed by myeloid dendritic cells (DC), macrophages, placental trophoblasts, myocardial endothelium and cortical thymic epithelial cells, 21,22 whereas PD-L2 is expressed by DC, macrophages, placental endothelium and medullary thymic epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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“…In a mouse model of chronic infection, anti-PD-L1 antibody treatment reinvigorates exhausted T-cells, but only produces minimal memory, and T-cells reacquire the exhausted phenotype with persistent antigen, suggesting a limited duration of antitumor T-cell responses to blockade of the PD-1/PD-L1 axis (60). In addition to the well-established role of PD-1 on T-cells, a recent study demonstrates that PD-1 has an intrinsic effect in melanoma cells (61). A portion of human melanoma cells express PD-1.…”

Section: Pd-1 In Cancermentioning

confidence: 99%

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

Rausch¹,

Hastings

2017

Cutaneous Melanoma: Etiology and Therapy

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Abstract:Immune checkpoint blockade has revolutionized the treatment of patients with advanced melanoma and many other cancers. Blockade of inhibitory receptors, CTLA-4 and PD-1, enhances T-cell-mediated antitumor immune responses, leading to improved survival and durable responses in patients. Based on their mechanism of action, immune checkpoint inhibitors can also induce immune-related adverse events that require careful monitoring and prompt treatment. Despite these successes, only a fraction of patients benefit from immune checkpoint blockade. Basic science approaches and clinical experience are defining predictive biomarkers to identify patients most likely to respond to therapy as well as mechanisms of resistance that limit responses in certain tumors or shorten the duration of response. New approaches and combination therapies are under development to broaden the clinical impact of immune checkpoint blockade by overcoming resistance to therapy and limiting adverse events.

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Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

Cited by 531 publications

References 33 publications

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

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