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; Etō, Morifusa; Tamada, Koji

doi:10.1016/s1569-9056(19)30439-7

Cited by 18 publications

(25 citation statements)

References 28 publications

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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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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 expected better clinical efficacy with anti‐PD‐1 Ab (nivolumab) plus carboplatin/paclitaxel/bevacizumab than anti‐PD‐L1 based on the strength of preclinical findings and previously described clinical studies. Preclinical studies indicated that combined PD‐L1/PD‐L2 blockade on dendritic cells augmented T cell proliferation and cytokine production more effectively than PD‐L1 blockade alone, 19 and that anti‐PD‐1 Abs might be more effective, by blocking the interaction between PD‐1 and both PD‐L1/PD‐L2, than anti‐PD‐L1 Abs, which only block the PD‐1/PD‐L1 interaction 20 …”

Section: Discussionmentioning

confidence: 99%

Five‐year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non‐small‐cell lung cancer

Kanda¹,

Ohe²,

Goto³

et al. 2020

Cancer Science

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Combination antiprogrammed death 1/programmed death‐ligand 1 Ab and platinum‐based chemotherapy is standard first‐line treatment for advanced non‐small‐cell lung cancer without targetable oncogene alterations. We describe the long‐term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non‐small‐cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first‐line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first‐line); arm C, 4‐6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first‐line); and arm D, docetaxel (second‐ or third‐line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow‐up period was 57.9 months. Median progression‐free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+‐47.8), 11.8 (1.4‐65.1+), 40.7 (5.3‐60.8+), and 3.2 (1.9‐10.9) months, and 5‐year progression‐free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0‐55.4), 28.5 (14.6‐66.2+), not reached (24.2‐67.4+), and 12.5 (9.8‐16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment‐related deaths occurred. Nivolumab and platinum‐based chemotherapy combinations showed long‐term tolerability. A moderate proportion of patients in arm C showed 5‐year progression‐free and overall survival.

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“…The in vivo study focused on the mechanism of how the ligand for PD‐1 regulates antitumor immunity revealed that the TAM‐derived PD‐L1 contributes predominantly to suppress antitumor immunity than the host‐derived one. Further investigation indicated the importance of TAM‐expressed PD‐L2, another ligand for PD‐1, in the suppression of antitumor immunity . In fact, the immunosuppressive activity of TAMs is largely depended on the cytokines liberation that acts on T cells and the subsets.…”

Section: Immunity In Cancermentioning

confidence: 99%

Crosstalk between cancer and immune cells: Role of tumor‐associated macrophages in the tumor microenvironment

et al. 2019

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Tumor microenvironment is a complex system that contains multiple cells and cytokines. Among the multiple immune cells, macrophage is particularly abundant and plays an important role throughout the tumor progression process, namely, tumor‐associated macrophage (TAM) in this special tumor microenvironment. Many kinds of cytokines from TAMs and other immune cells in tumor niche are involved in the linkage of inflammation, immunity and tumorigenesis. Inflammatory responses induced by TAMs are crucial to tumor development of different stages. This review highlights the critical role of TAMs in the linkage of inflammation, immunity, and cancer. It outlines the molecules of inflammatory cytokines, chemokines, and growth factors mainly from TAMs in tumor microenvironment and their functions in tumor development during the major issues of angiogenesis, chronic inflammation, and immune suppression. Additionally, the signaling pathways involved in tumor progression and the crosstalk between them are also summarized.

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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 18 publications

References 28 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

Five‐year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non‐small‐cell lung cancer

Crosstalk between cancer and immune cells: Role of tumor‐associated macrophages in the tumor microenvironment

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