Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

Merelli, Barbara; Massi, Daniela; Cattaneo, Laura; Mandalà, Mario

doi:10.1016/j.critrevonc.2013.08.002

Cited by 154 publications

(120 citation statements)

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“…immune cells in the tumor microenvironment were also evaluated. Detection of immunosuppressive markers including PD-L1, CTLA-4, and IDO has been reported for various tumor types [4,[15][16][17][18][19][20][21][22][23][24][25][26][27]. In our study, the positive expression of PD-L1, CTLA-4, and IDO was noted in 43.6, 65.8, and 47.7 % of the cases, respectively.…”

Section: Discussionmentioning

confidence: 54%

“…An immunogenic interaction exists between the host and the tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease [3]. Recently, immunotherapeutic agents targeting immunosuppressive proteins such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and killer cell Ig-like receptor have been investigated as potential treatments for cancer [4]. Among these immunotherapeutic agents, anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have shown promising clinical efficacy towards melanoma as well as several other cancer types [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

et al. 2014

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Background There are few data on the clinical implications of immunosuppressive protein expression in tumors and immune cell infiltration within the tumor microenvironment in patients with gastric cancer (GC). Methods In this study, 243 patients with curatively resected GC were included. The levels of immunosuppressive protein expression [programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO)] in tumors and the densities of immune cells [CD3(?), CD4(?), CD8(?), or PD-1(?) cells] within the tumor microenvironment were measured using immunohistochemical analysis. Results Positive PD-L1, CTLA-4, and IDO expression was observed in 43.6, 65.8, and 47.7 % of the patients, respectively. Expression of PD-L1, CTLA-4, and IDO was related to less advanced stage, intestinal type, and well/ moderately differentiated adenocarcinoma (P \ 0.05). PD-L1 expression was related to better disease-free survival (DFS) and overall survival (OS) in GC [PD-L1(?) vs. PD-L1(-) tumors: 5-year DFS rate, 82.6 vs. 66.9 %; 5-year OS rate, 83.0 vs. 69.1 % (P values \0.05)]. Survival outcomes were also better in patients with a higher density of CD3(?) cells within the tumor microenvironment than in those with a lower density of CD3(?) cells [5-year DFS rate, 80.9 vs. 67.0 %; 5-year OS rate, 82.5 vs. 68.0 % (P values \0.05)]. In multivariate analysis, these two immune markers had a prognostic impact on survival, independent of other clinical variables. Conclusions GC patients with immunosuppressive protein expression (PD-L1, CTLA-4, or IDO) had distinct clinicopathological characteristics. PD-L1(?) expression and a high-CD3 tumor microenvironment are favorable prognostic markers in GC.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

et al. 2014

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“…Immunotherapy targeting the immune checkpoint programmed death‐1 (PD‐1)/PD‐ligand (L) 1 axis has been used to treat various cancers including non‐small‐cell lung cancer, melanoma, renal cell carcinoma and Hodgkin lymphoma 6, 7, 8, 9, 10. Recently, PD‐1/PD‐L1 inhibitors were also used to treat patients with advanced MPM, and several clinical trials are ongoing 11, 12.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

Hsu

Miao

Wang

et al. 2018

J Cellular Molecular Medi

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Although tumour PD‐L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD‐L1 axis in various cancers, the regulation of PD‐L1 (CD274) expression is unclear. Yes‐associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down‐regulates PD‐L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD‐L1 protein expression compared to H290, MS‐1 and H28 cells. In H2052 and 211H cells, PD‐L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD‐L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD‐L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD‐L1 enhancer region encompassing 2 putative YAP‐TEAD‐binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD‐L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi‐square). We conclude that PD‐L1 is correlated with YAP expression, and inhibition of YAP down‐regulates PD‐L1 expression in human MPM. Further study of how YAP regulates PD‐L1 in MPM is warranted.

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“…3). Unlike conventional chemotherapy or molecular targeted therapy, anti-PD-1 antibody achieves its antitumor effect by restoring the original potential of the natural human immune system as a powerful and precise weapon against cancer cells [11][12][13][14][15][16][17][18][19][20][21][22]. Antibodies against PD-L1 expression in the cancer tissue are believed to have a similar effect [23].…”

mentioning

confidence: 99%

Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update

Kudo¹

2016

Liver Cancer

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releasing molecules such as perforin and granzymes (the effector phase) (fig 1) [10]. Moreover, recognition of TAAs by T cell receptors (TCR) triggers the release of interferon gamma (IFN-γ) and other cytokines by CD8-positive T cells in an attempt to attack the cancer. However, tumor cells protect themselves by expressing IFN-γ induced PD-L1 or PD-L2, which binds to PD-1. When this happens, PD-1/PD-L1 binding attenuate the antitumor immune response, thereby weakening the attacking power of the T cells. This is called immune escape or immune tolerance ( fig. 2). The anti-PD-1 antibody blocks PD-1 on activated T cells from binding to PD-L1 or PD-L2 on APCs or tumor cells. This removes the "brake" on the immune system and restores the ability of T cells to attack tumor cells ( fig. 3). Unlike conventional chemotherapy or molecular targeted therapy, anti-PD-1 antibody achieves its antitumor effect by restoring the original potential of the natural human immune system as a powerful and precise weapon against cancer cells [11][12][13][14][15][16][17][18][19][20][21][22]. Antibodies against PD-L1 expression in the cancer tissue are believed to have a similar effect [23]. The recognition of "immuno-oncology" using immune checkpoint inhibitors was considered the "Breakthrough of the Year" by the American journal Science in 2013, and immuno-oncology has been widely publicized. PD-L1 also serves as a biomarker that predicts the response to anti-PD-1 antibody [24]. In addition, Kupffer-phase Sonazoid contrast-enhanced ultrasonography is an effective imaging method for predicting the response to treatment with anti-PD-1 antibody [25]. Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma (HCC)Promising results from an interim analysis of a phase I/II trial of the anti-PD-1 antibody nivolumab (CheckMate-040 trial dose-escalation cohort) were presented at the

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Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

Cited by 154 publications

References 88 publications

Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

Inhibition of yes‐associated protein down‐regulates PD‐L1 (CD274) expression in human malignant pleural mesothelioma

Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update

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