Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment

Umezu, Daisuke; Okada, Nana J.; Sakoda, Yukimi; Adachi, Keishi; Ojima, Toshiyasu; Yamaue, Hiroki; Eto, Masatoshi; Tamada, Koji

doi:10.1007/s00262-018-2263-4

Cited by 49 publications

(29 citation statements)

References 29 publications

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“…To our knowledge, this is the first report to directly show the functional consequence of the immunosuppressive role of PD-L2 in a human model, although two reports recently proved the antitumor activity of PD-L2 using a preclinical animal model [44,47]. In the present study, using tumor antigen-specific CTL clone, we clearly showed that anti-PD-L2 mAb significantly enhanced the cytotoxicity of CTLs against GC cell lines expressing PD-L2 (Fig.…”

Section: Discussionsupporting

confidence: 60%

Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer

et al. 2020

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Background Gastric cancer (GC) patients with PD-L1-negative tumor occasionally have a favorable response to anti-PD-1 mAb. The aim of the present study was to investigate the regulatory mechanism and immunosuppressive role of PD-L2 in GC. Methods We used immunohistochemistry to evaluate the expression of PD-L2 in primary tumors from 194 patients with GC. The mechanism of PD-L2 expression was assessed in TCGA stomach adenocarcinoma tissue dataset and in vitro assay using GC cell lines. The immunosuppressive role of PD-L2 was evaluated by cytotoxicity of CTL clone against PD-L2 expressing GC cells. Results PD-L2 was expressed on tumor cells (TCs) of 28.4% patients and PD-L2 expression on TCs was significantly associated with tumor progression. TCGA dataset revealed that IFN-γ and, to a lesser extent, IL-4 signature significantly correlated with PD-L2 expression. In vitro assay showed that IFN-γ and, also to a lesser extent, IL-4 can upregulate PD-L2 expression on GC cells. Anti-PD-L2 mAb significantly enhanced the cytotoxicity of CTL clone against GC cell lines expressing PD-L2. Conclusions PD-L2 is expressed on GC cells and PD-1/PD-L2 interaction are functionally involved in anti-tumor CTL activities. PD-L2 expression should be considered when determining the optimal immunotherapy for GC.

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Section: Discussionsupporting

confidence: 60%

Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer

et al. 2020

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“…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 other TME types could be reasonable evidence that type 1 tumors might benefit better from anti‐PD‐1 therapies than from anti‐PD‐L1 therapies in the clinical context . Further clinical evaluation is warranted to support this hypothesis.…”

Section: Discussionmentioning

confidence: 93%

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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“…ICB treatment primarily targets programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Sharma et al, 2017). Programmed cell death-ligand 2 (PD-L2) was found to play a role in the regulation of anti-tumor immunity (Umezu et al, 2019). Multiple studies have shown that tumor mutational burden (TMB) may be a surrogate for overall neoantigen load, and it is correlated with clinical benefit from multiple checkpoint inhibitors (Rizvi et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

Guo

Zhu

et al. 2019

eLife

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Cutaneous melanoma (CM) is a life-threatening form of skin cancer. Prognostic biomarkers can reliably stratify patients at initial melanoma diagnosis according to risk, and may inform clinical decisions. Here, we performed a retrospective, cohort-based study analyzing genome-wide DNA methylation of 461 patients with CM from the TCGA database. Cox regression analyses were conducted to establish a four-DNA methylation signature that was significantly associated with the overall survival (OS) of patients with CM, and that was validated in an independent cohort. Corresponding Kaplan–Meier analysis displayed a distinct separation in OS. The ROC analysis confirmed that the predictive signature performed well. Notably, this signature exhibited much higher predictive accuracy in comparison with known biomarkers. This signature was significantly correlated with immune checkpoint blockade (ICB) immunotherapy-related signatures, and may have potential as a guide for measures of responsiveness to ICB immunotherapy.

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Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment

Abstract: PD-L1 expressed on tumor cells and bone marrow-derived hematopoietic cells, as well as PD-L2 inducibly expressed on tumor-associated macrophages, play an important role in the suppression of anti-tumor immune responses.

Cited by 49 publications

References 29 publications

Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer

Immune suppression caused by PD-L2 expression on tumor cells in gastric 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

A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma

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