Clinical relevance of CD70 expression in resected pancreatic cancer: Prognostic value and therapeutic potential

Nakamura, Kota; Sho, Masayuki; Akahori, Toshikazu; Nishiwada, Satoshi; Kunishige, Tomohiro; Nakagawa, Kenji; Nagai, Minako; Takagi, Tadataka; Terai, Taichi; Ikeda, Naoya

doi:10.1016/j.pan.2021.01.013

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…To follow, we show that CD70 silencing significantly reduce tumor burden and volume, and significantly increases survival time, with some animals showing no signs of disease up until the end of the experiment. These data represent similar findings to that seen in the literature, indicating that CD70 may play a crucial role in tumor-initiating cells in multiple cancers (Liu et al 2018;Nakamura et al 2021). To better understand the cellular pathways and programs involving CD70, we carried out GSEA using RNAseq of our CD70-silenced cell lines.…”

Section: Discussionsupporting

confidence: 87%

Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

Seyfrid

Maich

et al. 2021

Preprint

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Purpose: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of brain tumor initiating cells (BTICs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here we identify CD70 as a potential therapeutic target for recurrent GBM BTICs. Experimental Design: In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We utilize CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate the role of CD70 in GBM. Next, we developed and tested an anti-CD70 CAR-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples. Results: CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations. Conclusion: CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable poly-therapeutic avenue to co-target both GBM and its TIME.

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Section: Discussionsupporting

confidence: 87%

Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

Seyfrid

Maich

et al. 2021

Preprint

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“…These data represent similar findings to that seen in the literature, indicating that CD70 may play a crucial role in tumor-initiating cells in multiple cancers. 105 106 To better understand the cellular pathways and programs involving CD70, we carried out GSEA using RNAseq of our CD70-silenced cell lines. We were able to contribute to the functional understanding of CD70 by showing that, as previously noted in RCC and other cancers, CD70 plays a role in controlling hypoxia.…”

Section: Discussionmentioning

confidence: 99%

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

Seyfrid

Maich

Shaikh

et al. 2022

J Immunother Cancer

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PurposeGlioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, we identify CD70 as a potential therapeutic target for recurrent GBM CSCs.Experimental designIn the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We use CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate CD70’s role in GBM. Next, we developed and tested an anti-CD70 chimeric antigen receptor (CAR)-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples.ResultsCD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations, notably putative M1 macrophages and CD4 T cells.ConclusionCD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

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“…Upon silencing of CD70 in glioblastoma cell lines, expression levels of EMT-associated genes, SOX2 and CD44, decreased, resulting in inhibition of tumor growth and migration [95]. In addition, it was shown that β-catenin was significantly reduced after siRNA-mediated knock-down of CD70 expression in human pancreatic cell lines, as well as other EMT-related genes, such as Vimentin, Snail and Slug [97]. In melanoma, CD70 expression led to MAPK activation and RhoE overexpression, thereby promoting tumor migration [91].…”

Section: Signaling In Solid Tumorsmentioning

confidence: 99%

The CD70-CD27 axis in oncology: the new kids on the block

Flieswasser

Eynde

Audenaerde³

et al. 2022

J Exp Clin Cancer Res

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The immune checkpoint molecule CD70 and its receptor CD27 are aberrantly expressed in many hematological and solid malignancies. Dysregulation of the CD70-CD27 axis within the tumor and its microenvironment is associated with tumor progression and immunosuppression. This is in contrast to physiological conditions, where tightly controlled expression of CD70 and CD27 plays a role in co-stimulation in immune responses. In hematological malignancies, cancer cells co-express CD70 and CD27 promoting stemness, proliferation and survival of malignancy. In solid tumors, only expression of CD70 is present on the tumor cells which can facilitate immune evasion through CD27 expression in the tumor microenvironment. The discovery of these tumor promoting and immunosuppressive effects of the CD70-CD27 axis has unfolded a novel target in the field of oncology, CD70.In this review, we thoroughly discuss current insights into expression patterns and the role of the CD70-CD27 axis in hematological and solid malignancies, its effect on the tumor microenvironment and (pre)clinical therapeutic strategies.

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Clinical relevance of CD70 expression in resected pancreatic cancer: Prognostic value and therapeutic potential

Cited by 8 publications

References 30 publications

Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment

The CD70-CD27 axis in oncology: the new kids on the block

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