Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer

Jin, Sheng; Fang, Wenfeng; Yu, Juan; Chen, Nan; Zhan, Jie; Ma, Yuxiang; Yang, Yunpeng; Huang, Yan; Zhao, Hongyun; Zhang, Li

doi:10.1038/srep20090

Cited by 159 publications

(146 citation statements)

References 41 publications

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“…Furthermore, previous studies have used different antibodies and various cut-offs to define high and low expression of PD-L1 and PD-1, respectively, making it problematic to compare the results. Finally, several factors have been reported to affect the expression of PD-1 and PD-L1, including chemotherapy 52 , 53 and radiotherapy. 22 However, in the present cohort, only 61 (29,8%) of patients with rectal cancer received neoadjuvant treatment, and we found similar results regarding the prognostic value of the investigated biomarkers when excluding neo-adjuvant treated rectal cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

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Section: Discussionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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“…Beyond anticipated gastrointestinal and cutaneous toxicities, the emergence of serious neurologic events related to pareneoplastic syndromes affecting central and peripheral nervous systems, deserves attention. A fatal event of myasthenia gravis with combination therapy and three cases of limbic encephalitis (two in the monotherapy and one in the dual regimens) were reported, one of which, occurring in the monotherapy arm, was grade 4 and resistant to steroid administration.Cytotoxic treatment and radiotherapy can promote antigenic exposure and microenvironment remodeling, favoring immune checkpoint inhibitor activity 18,81,82. A randomized phase II study (STIMULI, NCT02046733) is evaluating the impact of combined ipilimumab-nivolumab on OS after completion of standard chemoradiation in LD-SCLC(Table 2).…”

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confidence: 99%

“…11 Not only is the assumption concerning the theoretical cellular distribution of PD-1, PD-L1 and PD-L2 partial and imprecise, 12 but in addition their expression is M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 prone to dynamic induction, notably upon exposure to cytokines such as interferon gamma. 13 Moreover, spatial, 14,15,16 temporal and therapeutic 17,18 factors can impact PD-L1 expression in the tumor microenvironment. All these elements highlight the dynamic nature of PD-L1 and cloud a clear understanding of PD-1/PD-L1 blockade mechanisms.…”

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confidence: 99%

Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC

Facchinetti

Marabelle

Rossi

et al. 2016

Journal of Thoracic Oncology

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SCLC and malignant pleural mesothelioma (MPM) are historically characterized by a disappointing lack of significant therapeutic breakthroughs for novel agents, and both malignancies represent true unmet medical needs. Given the promising results of anti-cytotoxic T-lymphocyte associated protein-4 and anti-programmed cell death-1/programmed death ligand-1 antibodies in the treatment of advanced NSCLCs, these immune checkpoint inhibitors are now also under investigation in SCLC and MPM, as well as in thymic epithelial tumors (TETs). Here, we review the biological and clinical rationale for immune checkpoint inhibition in SCLC, MPM, and TETs and present preliminary clinical results with available antibodies. Immunotherapeutic perspectives for these malignancies in terms of novel agents currently under evaluation or anticipated in the near future are also discussed. Current immune checkpoint blockers targeting cytotoxic T-lymphocyte associated protein-4 and the programmed cell death-1/programmed death ligand-1 axis, administered alone or in combination and as multimodality treatment, are likely to be a valuable addition to the therapeutic array for managing SCLC and MPM; studies in TETs, which are currently in their infancy, are merited. Close attention to potential toxicities will be important to the success of such strategies in these settings.

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“…Furthermore, there is clear plasticity in PD-L1 expression. Several studies across several tumor types have shown changes in PD-L1 expression on tumor cells after treatment with chemotherapy, begging the question of how to best pair or sequence chemotherapies to upregulate PD-L1 expression and enhance efficacy of checkpoint inhibition [17].…”

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confidence: 99%

Five New Therapies or Just One New Treatment? A Critical Look at Immune Checkpoint Inhibition in Urothelial Cancer

2017

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" It is clear that we are just at the beginning of the new immune era in the treatment of cancer.The field is ripe for progress in studying further combinations that enhance the activity of the immune system and overcome pathways of resistance " Physicians have been enlivened by the first major breakthrough in over 30 years in metastatic urothelial cancer (UC) with the approval of five new therapeutics involved in immune checkpoint blockade. These newly approved agents in UC are monoclonal antibodies blocking PD-L1 including atezolizumab, durvalumab and avelumab, or monoclonal antibodies against PD-1 including nivolumab and pembrolizumab. PD-1, a checkpoint protein present on activated T cells, interferes with T-cell antigen receptor mediated signaling to act as an 'off-switch' and thus avoid immune attack on self-cells [1]. PD-L1 protein is present on normal cells and binds PD-1, which allows this downregulation of T-cell response. However, many cancer cells also express PD-L1, allowing them to masquerade as normal cells and avoid immune-mediated attack. By interfering with the PD-1/PD-L1 interaction, these drugs allow for a heightened immune attack on cancer cells.The concept of immune-mediated therapy is not new in UC. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has been used for four decades in superficial bladder cancer and is thought to allow a more robust local inflammatory response via intravesicular treatment [2,3]. IFN-α has also been used as an immune modulatory approach, given both intravesically in combination with BCG [4,5], and systemically in combination with chemotherapy, with variable activity reported [6]. A more recent gene therapy approach using an IFN-α-expressing adenovirus has resulted in more sustained levels of IFN-α in the bladder [7]. Ipilimumab, an anti-CTLA antibody, has been explored in localized bladder cancer and resulted in tumor immune infiltrates and pathological clinical responses in 3 of 12 patients treated with neoadjuvant ipilimumab [8].Atezolizumab was first granted accelerated US FDA approval in May 2016 following front line platinum-based therapy with an observed response rate of 15%, which was an improvement over the 10% historic control [9]. Activity was observed in both PD-L1 positive and negative tumors, resulting in approval regardless of PD-L1 status [9]. Of the 45 responders, 38 patients had ongoing durable responses at 11.7 months. Subsequently, nivolumab, durvalumab, avelumab and pembrolizumab were approved with similar response rates around 15-21% and trend toward durable responses in each trial [10][11][12]. Pembrolizumab is currently the only immune checkpoint inhibitor with Level I evidence from a Phase III trial showing improved survival compared with single agent taxanes. A recent update on a Phase III study suggests atezolizumab as a second-line therapy has not achieved its survival end point [13]. Further data from this trial are needed to determine whether this was due to trial design, due to crossover of the taxane...

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Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer

Cited by 159 publications

References 41 publications

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC

Five New Therapies or Just One New Treatment? A Critical Look at Immune Checkpoint Inhibition in Urothelial Cancer

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