Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer

Shibahara, Daisuke; Tanaka, Kentaro; Iwama, Eiji; Kubo, Naoki; Ota, Keiichi; Azuma, Koichi; Harada, Taishi; Fujita, Jiro; Nakanishi, Yoichi; Okamoto, Isamu

doi:10.1016/j.jtho.2018.03.012

Cited by 31 publications

(28 citation statements)

References 41 publications

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“…In this study, a positive PD‐L2 expression was not associated with any clinicopathological characteristics, but it was significantly high in type 1, among the TME subtypes. Recent basic research showed that the expression of PD‐L2, as well as PD‐L1, in EGFR ‐mutated or ALK ‐rearranged NSCLC could be induced extrinsically by interferon‐γ and intrinsically by oncogenic signaling . The tendency of EGFR ‐mutated NSCLC with high PD‐L1 expression to coexpress PD‐L2 through extrinsic or intrinsic mechanisms remains elusive in the context of basic research.…”

Section: Discussionmentioning

confidence: 99%

“…Recent basic research showed that the expression of PD-L2, as well as PD-L1, in EGFR-mutated or ALK-rearranged NSCLC could be induced extrinsically by interferon-γ and intrinsically by oncogenic signaling. 33 The tendency of EGFR-mutated NSCLC with high PD-L1 expression to coexpress PD-L2 through extrinsic or intrinsic mechanisms remains elusive in the context of basic research. However, the observation of highest PD-L2 coexpression in type 1 tumors compared to F I G U R E 4 Representative case of non-small cell lung cancer with altered tumor microenvironment and response to epidermal growth factor receptor-tyrosine kinase inhibitor EGFR-TKI) before and after developing acquired resistance to the initial EGFR-TKI therapy.…”

Section: Discussionmentioning

confidence: 99%

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Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

et al. 2019

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We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8+ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

et al. 2019

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“…Immune checkpoints are critical modulators of the immune system's function. Immunotherapies targeting various immune checkpoints, including programmed death 1 (PD‐1), programmed death‐ligand 1 (PD‐L1), Cytotoxic T‐Lymphocyte Antigen 4 (CTLA4) and programmed cell death 1 ligand 2 (PD‐L2), have a beneficial impact on NSCLC 7‐9 . Besides, as front‐line therapeutic agents, these immune inhibitors have shown promising results compared with the other unsuccessful treatments.…”

Section: Introductionmentioning

confidence: 99%

Characterizing heterogeneity of non‐small cell lung tumour microenvironment to identify signature prognostic genes

Chen

Qian

et al. 2020

J Cellular Molecular Medi

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“…The interaction between PD‐L2 and PD‐1 also inhibits T‐cell activation. IFN‐γ can also induce expression of PD‐L2, 118 although only 13% of NSCLC is PD‐L2 positive, and more than half of the PD‐L2‐positive tumors (46 of 85; 54.1%) were PD‐L1 negative 119 . PD‐L2 can compete with PD‐L1 to bind to PD‐1 with a two‐ to six‐fold higher affinity.…”

Section: The Undetermined Problems Of Pd‐l1mentioning

confidence: 99%

“…PD‐L2 can compete with PD‐L1 to bind to PD‐1 with a two‐ to six‐fold higher affinity. PD‐L2 expression may be a supplementary biomarker of immunotherapy in patients with PD‐L1‐negative NSCLC 118 …”

Section: The Undetermined Problems Of Pd‐l1mentioning

confidence: 99%

PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer?

Dong

Zhao

et al. 2021

The Journal of Gene Medicine

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PD‐L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD‐1 and PD‐L1 inhibitors have induced durable and effective responses in patients with advanced non‐small cell lung cancer, confirmed by multiple clinical trials and real‐world studies. Different clinical trials, involving both PD‐1/PD‐L1 inhibitors alone and combination regimens, adopted either PD‐L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first‐line setting, PD‐L1 of 50% or more as a cut‐off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first‐line treatments. In the second‐line setting, although patients can benefit from nivolumab regardless of PD‐L1 expression, both PD‐L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD‐L1 were low in most circumstances; however, PD‐L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first‐line monotherapies. Higher PD‐L1 or TMB was associated with greater efficacy for atezolizumab as a second‐line monotherapy.

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Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer

Cited by 31 publications

References 41 publications

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Characterizing heterogeneity of non‐small cell lung tumour microenvironment to identify signature prognostic genes

PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer?

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