PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse

Zheng, Bingxin; Ren, Tingting; Huang, Yi; Sun, Kunkun; Wang, Shidong; Bao, Xiaoyong; Liu, Kuisheng; Wei, Guo

doi:10.1186/s13045-018-0560-1

Cited by 108 publications

(108 citation statements)

References 45 publications

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“…As shown in Figure-4A-B, the positivity rate of PD-L1 in osteosarcoma specimen was 35.5% (22/62) and the positivity rate was not so high as melanoma, breast cancer and lung carcinoma, which was reported in our previous study [26]. Haematoxylin and eosin staining revealed the tumor had destruction of cortical bone and invasion of the surrounding soft tissue could be seen.…”

Section: Pd-l1 Is Located At Surface Of Osteosarcoma Exosomessupporting

confidence: 60%

“…Staining intensity was classi ed as follows: 0, no staining or staining in < 10% of tumor cells; 1+, weak to moderate staining in 10 to 20% of tumor cells; 2+, strong staining in 10 to 20% of tumor cells or weak staining in 20 to 50% of tumor cells; 3+, moderate to strong staining in 20 to 50% of tumor cells or staining in 50% of tumor cells. The immunostaining assessment was conducted by two independent pathologists without any previous knowledge of the clinical characteristics and outcomes [26]. The primary antibodies were as follows: (1) Mouse anti-PD-L1 (sc-293425, Santa Cruz, CA, USA), (2) Rabbit monoclonal anti-E-cadherin (ab194982), (3) Rabbit polyclonal anti-N-cadherin (ab18203), (4) Rabbit monoclonal anti-vimentin (ab92547).…”

Section: Immunohistochemistry Analysismentioning

confidence: 99%

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Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

Wang¹,

Zhang²,

Sun³

et al. 2020

Preprint

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Abstract Background Recent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how the exosome influences the osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. Methods We examined serum exosomes from 70 patients with osteosarcoma, 9 patients with benign tumors and 22 healthy donors. Osteosarcoma-derived exosomes and exosomal-PD-L1 were functionally evaluated using in vivo and in vitro models. Results The characteristics of serum exosomes of OS patients and OS cell line exosomes were confirmed by several methods. Bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Meanwhile, exosomes derived from OS cell line and serum of OS patients could induce osteosarcoma migration and invision in vitro. Then, we confirmed PD-L1 existing in Sr-exosomes of patients with osteosarcoma and higher level of Sr-exosomal PD-L1 in OS patients compared to healthy donors and patients with benign tumor. Furthermore, exosomal-PD-L1 derived from osteosarcoma promoted the pulmonary metastasis, which was demonstrated in the osteosarcoma metastatic model. Conclusion We confirm that osteosarcoma releases the exosomes carrying PD-L1 on their surface and induces the pathogenesis of pulmonary metastasis for OS patients.

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Section: Pd-l1 Is Located At Surface Of Osteosarcoma Exosomessupporting

confidence: 60%

Section: Immunohistochemistry Analysismentioning

confidence: 99%

Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

Wang¹,

Zhang²,

Sun³

et al. 2020

Preprint

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“…The role of PD‐L2 in the tumor microenvironment is less understood compared to that of PD‐L1 in sarcomas. Zheng et al first examined the expression of PD‐L2 in 234 patients with musculoskeletal tumors including 127 cases of patients with SS, and 26 cases (20.5%) of SS were positive for PD‐L2 by immunohistochemistry. However, the prognostic impact of PD‐L1 and PD‐L2 in SS remains unclear and further experiments are required to show the mechanism underlying the association among PD‐L1, PD‐L2, and prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…The role of PD-L2 in the tumor microenvironment is less understood compared to that of PD-L1 in sarcomas. Zheng et al 36 pro-tumoral M2-like macrophages. 37 M2-like macrophages may be involved in tumor progression by promoting angiogenesis, suppressive adaptive immunity, tumor cell proliferation, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the tumor immune microenvironment in synovial sarcoma

et al. 2018

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The association between the immune status within the tumor microenvironment and prognosis in synovial sarcoma is not well understood. We aimed to investigate the tumor immune microenvironment and analyze its prognostic impact for patients with synovial sarcoma. A total of 36 primary patients who were treated in our institution were retrospectively evaluated. Infiltration of lymphocytes (CD4+, CD8+, and FOXP3+), CD163+ macrophages, and expression of human leukocyte antigen (HLA) class I and programmed death ligand 1 (PD‐L1) were evaluated by immunohistochemistry. Moreover, we investigated PD‐L1 and programmed death ligand 2 (PD‐L2) mRNA expression in 19 of the 36 cases, using real‐time PCR. The Kaplan‐Meier method was used to estimate overall survival and progression‐free survival. Infiltration of lymphocytes and macrophages varied among the patients. Furthermore, the expression of HLA class I was negative or downregulated in 11 specimens. No PD‐L1 expression was observed using immunohistochemistry. Moreover, although PD‐L1 mRNA expression was observed in 18 of 19 specimens, the expression level was low. A higher infiltration of CD8+ or FOXP3+ lymphocytes in patients was associated with a favorable overall survival. In addition, a higher infiltration of CD163+ macrophages indicated a significantly worse overall and progression‐free survival. Infiltration of CD4+ lymphocytes, HLA class I, PD‐L1, and PD‐L2 expression were not associated with patient prognosis. This represents the first report investigating the tumor immune microenvironment as a prognostic factor in synovial sarcoma, indicating that CD163+ macrophages are associated with tumor progression. Our results underscore the clinical significance of the tumor immune microenvironment in synovial sarcoma.

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“…PD-1 upregulation is associated with T cell exhaustion that inhibits T cell functions upon binding to its ligands, such as PD-L1 and PD-L2 [23]. PD-L1 is widely expressed in various solid tumors [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

Qin

Zhao

Chen

et al. 2020

Preprint

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Background: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Methods: Here, we designed a dominant-negative form of PD-1 , dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. Results: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1 + tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. Conclusions: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

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PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse

Cited by 108 publications

References 45 publications

Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

Prognostic impact of the tumor immune microenvironment in synovial sarcoma

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

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