Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

Sayitoğlu, Ece Canan; Georgoudaki, Anna Maria; Chrobok, Michael; Özkazanç, Didem; Josey, Benjamin J.; Arif, Muhammad; Kusser, Kim; Hartman, Michelle; Chinn, Tamara M.; Potens, Renée; Pamukcu, Cevriye; Krueger, Robin; Zhang, Cheng Cheng; Mardinoğlu, Adil; Alici, Evren; Temple, H. Thomas; Sütlü, Tolga; Duru, Adil Doğanay

doi:10.3389/fimmu.2020.00040

Cited by 47 publications

(40 citation statements)

References 115 publications

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“…It was reported that the KLRK1 axis is becoming an emerging target in cancer immunotherapy [35,36], and the overexpression of CD226 or KLRK1 on NK cells resulted in e cient anti-sarcoma activity [37]. These studies were in accordance with our exploration to provide a molecular basis for the development of CD226-and KLRC4-KLRK1-targeted antitumor immune therapeutics.…”

Section: Discussionsupporting

confidence: 76%

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Tan

Liu

Wang

et al. 2020

Preprint

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Background: Breast cancer is one of the most frequently diagnosed cancers among women worldwide. Alterations in the tumor microenvironment (TME) have been increasingly recognized as key in the development and progression of breast cancer in recent years. To deeply comprehend the gene expression profiling of the TME and identify immunological targets, as well as determine the relationship between gene expression and different prognoses is highly critical. Results: The stromal/immune scores of breast cancer patients from The Cancer Genome Atlas were employed to comprehensively evaluate the TME. Although the TME did not correlate with the stages of breast cancer, it was closely associated with the subtypes of breast cancer and gene mutations (CDH1, TP53 and PTEN), and had immunological characteristics. Based on Gene Ontology (GO) functional enrichment analysis, the upregulated genes from the high vs low immune score groups were mainly involved in T cell activation, the external side of the plasma membrane, and receptor ligand activity. We further analyzed and screened the overlapping genes of the top 3 GO terms and upregulated differentially expressed genes (DEGs). Overall survival, time-dependent receiver operating characteristic (ROC), and protein-protein interaction (PPI) network analyses revealed that the genes of the top GO terms of the upregulated DEGs from the high vs low immune score groups exhibited better prognosis in breast cancer; 15 of them were related to good prognosis in breast cancer, especially CD226 and KLRC4-KLRK1.Conclusions: High CD226 and KLRC4-KLRK1 expression levels were identified and validated to correlate with better overall survival in specific stages or subtypes of breast cancer. CD226, KLRC4-KLRK1 and other new targets seem to be promising avenues for promoting antitumor targeted immunotherapy in breast cancer.

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Section: Discussionsupporting

confidence: 76%

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Tan

Liu

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…It was reported that the KLRK1 axis is becoming an emerging target in cancer immunotherapy [33,34], and the overexpression of CD226 or KLRK1 on NK cells resulted in e cient anti-sarcoma activity [35]. These studies were in accordance with our exploration to provide a molecular basis for the development of CD226-and KLRC4-KLRK1-targeted antitumor immune therapeutics.…”

Section: Discussionsupporting

confidence: 76%

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Tan

Liu

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Breast cancer is one of the most frequently diagnosed cancers among women worldwide. Alterations in the tumor microenvironment (TME) have been increasingly recognized as key in the development and progression of breast cancer in recent years. To deeply comprehend the gene expression profiling of the TME and identify immunological targets, as well as determine the relationship between gene expression and different prognoses is highly critical. Results The stromal/immune scores of breast cancer patients from The Cancer Genome Atlas were employed to comprehensively evaluate the TME. Although the TME did not correlate with the stages of breast cancer, it was closely associated with the subtypes of breast cancer and gene mutations (CDH1, TP53 and PTEN), and had immunological characteristics. Based on Gene Ontology (GO) functional enrichment analysis, the upregulated genes from the high vs low immune score groups were mainly involved in T cell activation, the external side of the plasma membrane, and receptor ligand activity. We further analyzed and screened the overlapping genes of the top 3 GO terms and upregulated differentially expressed genes (DEGs). Overall survival, time-dependent receiver operating characteristic (ROC), and protein-protein interaction (PPI) network analyses revealed that the genes of the top GO terms of the upregulated DEGs from the high vs low immune score groups exhibited better prognosis in breast cancer; 15 of them were related to good prognosis in breast cancer, especially CD226 and KLRC4-KLRK1. Conclusions High CD226 and KLRC4-KLRK1 expression levels were identified and validated to correlate with better overall survival in specific stages or subtypes of breast cancer. CD226, KLRC4-KLRK1 and other new targets seem to be promising avenues for promoting antitumor targeted immunotherapy in breast cancer.

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“…10 Open access of these properties, NK cells are an attractive modality for cancer therapy since they can respond to diverse stimuli. 11 In addition, NK cells have shown evidence of activity against STS in both preclinical models [12][13][14] and clinical trials. 15 Despite some early success, however, the results of adoptive NK therapy in the treatment of solid tumors, including sarcomas, have been largely disappointing, 16 and dysfunction/diminished cytotoxicity in a pattern similar to T cell exhaustion has emerged as a barrier to successful translation of NK immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

Judge

Darrow

Thorpe

et al. 2020

J Immunother Cancer

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PurposeGiven the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.Experimental designUsing prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody.ResultsTILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets.ConclusionIntratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS.

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Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

Cited by 47 publications

References 115 publications

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

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