Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1

Ziblat, Andrea; Iraolagoitia, Ximena L. Raffo; Nuñez, Sol Yanel; Torres, Nicolás I.; Secchiari, Florencia; Sierra, Jessica Mariel; Spallanzani, Raúl G.; Rovegno, Agustín Roberto; Secín, Fernando P.; Fuertes, Mercedes; Domaica, Carolina Inés; Zwirner, Norberto Walter

doi:10.3389/fimmu.2021.681615

Cited by 18 publications

(13 citation statements)

References 54 publications

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“…On the other hand, GSEA also reveals the relevance of CENPM to the immune in ltration pro le in ccRCC. Indeed, in ccRCC patients, NK cell in ltration in the circulation and tumour was found to be strongly associated with an immunosuppressive phenotype [31]. [32] Regulatory T cells are one of the major immunosuppressive cell types in malignancies and a potential target for immunotherapy [33].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma

Zhang

Liu

et al. 2022

Preprint

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Background: The response of advanced clear cell renal cell carcinoma (ccRCC) to immunotherapy is still not durable, suggesting that the immune landscape of ccRCC still needs to be refined, especially as some molecules that have synergistic effects with immune checkpoint genes need to be explored.Methods: The expression levels of CENPM and its relationship with clinicopathological features were explored using the ccRCC dataset from TCGA and GEO databases. Quantitative polymerase chain reaction (qPCR) analysis was performed to validate the expression of CENPM in renal cancer cell lines. ROC curves, Kaplan-Meier analysis, COX regression analysis and Nomogram construction were used to systematically evaluate the diagnostic and prognostic potential of CENPM in ccRCC. Besides, single gene correlation analysis, protein–protein interaction (PPI) network, genetic ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis (GSEA) were used to predict the biological behaviour of CENPM and the possible signalling pathways involved. Finally, a comprehensive analysis of the crosstalk between CENPM and immune features in the tumor microenvironment was performed based on the ssGSEA algorithm, the tumor immune dysfunction and exclusion (TIDE) algorithm, the TIMER2.0 database and the TISIDB database.Results: CENPM was significantly upregulated in ccRCC tissues and renal cancer cell lines and was closely associated with poor clinicopathological features and prognosis. Pathway enrichment analysis revealed that CENPM may be involved in the regulation of the cell cycle in ccRCC and may have some crosstalk with the immune microenvironment in tumors. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. Furthermore, the TISIDB database provides evidence that not only CENPM is positively associated with immune checkpoint genes such as CTLA4, PDCD1, LAG3, TIGIT, but also chemokines and receptors (such as CCL5, CXCL13, CXCR3, CXCR5) may be responsible for the malignant phenotype of CENPM in ccRCC. Meanwhile, predictions based on the TIDE algorithm support that patients with high CENPM expression have a worse response to immunotherapy.Conclusions: The upregulation of CENPM in ccRCC predicts a poor clinical outcome, and this malignant phenotype may be associated with its exacerbation of the immunosuppressive state in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma

Zhang

Liu

et al. 2022

Preprint

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“…However, it is also possible that tumors that developed more proficient strategies to subvert NK cell effector function exhibit higher tumor growth, resulting in lower disease-free and overall survival. TINK often are dysfunctional and display phenotypic alterations compared to NK cells from blood or from peritumoral tissue in different cancer types ( 8 , 9 , 11 ), including RCC ( 10 , 12 , 47 ). Using a mouse model, we previously demonstrated that TINK express PD-L1 and inhibit anti-tumor T cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…Although NK cells are critical for the elimination of nascent tumor cells (4,5), during the equilibrium phase (dormancy) between the tumor and the immune system NK cells seem to be dispensable (6). Moreover, once tumors escape from the immune system through a broad spectrum of immunosuppressive strategies that result in clinically apparent malignancies (7), tumor-infiltrating NK cells (TINK) become dysfunctional and display phenotypic alterations (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Tumor-Experienced Human NK Cells Express High Levels of PD-L1 and Inhibit CD8+ T Cell Proliferation

et al. 2021

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Natural Killer (NK) cells play a key role in cancer immunosurveillance. However, NK cells from cancer patients display an altered phenotype and impaired effector functions. In addition, evidence of a regulatory role for NK cells is emerging in diverse models of viral infection, transplantation, and autoimmunity. Here, we analyzed clear cell renal cell carcinoma (ccRCC) datasets from The Cancer Genome Atlas (TCGA) and observed that a higher expression of NK cell signature genes is associated with reduced survival. Analysis of fresh tumor samples from ccRCC patients unraveled the presence of a high frequency of tumor-infiltrating PD-L1+ NK cells, suggesting that these NK cells might exhibit immunoregulatory functions. In vitro, PD-L1 expression was induced on NK cells from healthy donors (HD) upon direct tumor cell recognition through NKG2D and was further up-regulated by monocyte-derived IL-18. Moreover, in vitro generated PD-L1hi NK cells displayed an activated phenotype and enhanced effector functions compared to PD-L1- NK cells, but simultaneously, they directly inhibited CD8+ T cell proliferation in a PD-L1-dependent manner. Our results suggest that tumors might drive the development of PD-L1-expressing NK cells that acquire immunoregulatory functions in humans. Hence, rational manipulation of these regulatory cells emerges as a possibility that may lead to improved anti-tumor immunity in cancer patients.

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“…For example, NK cell frequencies are associated with an altered patients’ survival in many tumor entities. NK cells highly infiltrating renal cell carcinoma (RCC) were dysfunctional in ex vivo cultures ( 14 , 55 , 56 ) ( Table 2 ) and showed an increased expression of inhibitory receptors and a downregulation of activating receptors. Furthermore, low numbers of NK cells in head and neck squamous cell carcinoma (HNSCC) were associated with insufficient tumor elimination, while higher numbers of NK cells at the tumor site correlated with an increased patients’ survival.…”

Section: Composition Of the Tumor Microenvironment And Nk Cellsmentioning

confidence: 99%

Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies

Seliger

Koehl

2022

Front. Immunol.

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Natural killer (NK) cells belong to the family of innate immune cells with the capacity to recognize and kill tumor cells. Different phenotypes and functional properties of NK cells have been described in tumor patients, which could be shaped by the tumor microenvironment. The discovery of HLA class I-specific inhibitory receptors controlling NK cell activity paved the way to the fundamental concept of modulating immune responses that are regulated by an array of inhibitory receptors, and emphasized the importance to explore the potential of NK cells in cancer therapy. Although a whole range of NK cell-based approaches are currently being developed, there are still major challenges that need to be overcome for improved efficacy of these therapies. These include escape of tumor cells from NK cell recognition due to their expression of inhibitory molecules, immune suppressive signals of NK cells, reduced NK cell infiltration of tumors, an immune suppressive micromilieu and limited in vivo persistence of NK cells. Therefore, this review provides an overview about the NK cell biology, alterations of NK cell activities, changes in tumor cells and the tumor microenvironment contributing to immune escape or immune surveillance by NK cells and their underlying molecular mechanisms as well as the current status and novel aspects of NK cell-based therapeutic strategies including their genetic engineering and their combination with conventional treatment options to overcome tumor-mediated evasion strategies and improve therapy efficacy.

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Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1

Cited by 18 publications

References 54 publications

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma

Tumor-Experienced Human NK Cells Express High Levels of PD-L1 and Inhibit CD8+ T Cell Proliferation

Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies

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