NK cell dysfunction with down-regulated CD16 and up-regulated CD56 molecules in patients with esophageal squamous cell carcinoma

Watanabe, Masashi; Kono, Koji; Kawaguchi, Yoshihiko; Matsuo, Yoshiki; Mimura, Kousaku; Maruyama, Takanori; Izawa, Shinichiro; Fujii, Hideki

doi:10.1111/j.1442-2050.2010.01073.x

Cited by 39 publications

(45 citation statements)

References 25 publications

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“…It has been already reported that the ADCC activities in advanced cancer patients were impaired due to several mechanisms, including NK cell dysfunction or immunosuppressive factors (8,23,24). As expected, we confirmed that the cetuximab-mediated and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals (Fig.…”

Section: Defucosylated Cetuximab-and Trastuzumab-mediated Adcc In Advsupporting

confidence: 77%

“…It is generally accepted that NK cells in cancer-bearing hosts are impaired by many mechanisms, including their reduced number, imbalances in their activating and inhibitory receptor, impaired activation signaling cascade as well as immunosuppressive cytokines (8,23,24). However, even in such a condition, the current study clearly indicated that the defucosylated mAbs can restore the impaired ADCC in advanced diseases.…”

Section: Discussionmentioning

confidence: 58%

“…It has been reported that Trastuzumab-mediated ADCC can be influenced by several factors including single nucleotide polymorphisms (SNPs) in the Fc gamma receptor (FcγR) genes (5-7) or natural killer (NK) cell dysfunction (8). In fact, the SNPs can alter the FcγR binding affinity to the therapeutic monoclonal antibodies (mAbs) and consequently resulted in impairment of the ADCC activity.…”

Section: Introductionmentioning

confidence: 99%

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Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer

et al. 2017

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Abstract. Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab-and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab-and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab-and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments. IntroductionAlthough improvement of systemic chemotherapy has been demonstrated in gastrointestinal (GI) tract cancer including gastric and colon cancer, the overall survival rate in patients with advanced stage is still poor (1). Therefore, it would be desirable to develop molecular target therapy more efficiently in GI-tract cancer. For example, for the human epidermal growth factor receptor (EGFR) related 2 (HER2)-overexpressing gastric cancer, Trastuzumab in combination with chemotherapy vs. chemotherapy alone for treatment of HER2-positive advanced gastric cancer (ToGA) trial concluded that anti-HER2 monoclonal antibody (trastuzumab) plus chemotherapy is a standard treatment option, in which trastuzumab plus chemotherapy showed better survival in comparison to chemotherapy alone (2).It is generally accepted that trastuzumab can act on gastric cancer cells through both anti-proliferative function directly to cancer cells and antibody-dependent cellular cytotoxicity (ADCC) activity via immune cells (3,4). It has been reported that Trastuzumab-mediated ADCC can be influenced by several factors including single nucleotide polymorphisms (SNPs) in the Fc gamma receptor (FcγR) genes (5-7) or natural killer (NK) cell dysfunction (8). In fact, the SNPs can alter the FcγR binding affinity to the t...

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Section: Defucosylated Cetuximab-and Trastuzumab-mediated Adcc In Advsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer

et al. 2017

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“…33,34 Similar changes and dysfunction were reported in NK cells isolated from patients with esophageal squamous cell carcinoma and non-small cell lung carcinoma, particularly in pleural effusion. 38,39 The downregulation of CD16 on NK cells has been shown to be driven by TGFβ and leads to conversion from cytotoxic to a more immunoregulatory phenotype similar to decidual NK cells. 30,38 In the current study, we found that NK cells downregulated their CD16 expression upon exposure to ovarian tumor microenvironment but this conversion was mitigated by PD-L1 blockade.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 The downregulation of CD16 on NK cells has been shown to be driven by TGFβ and leads to conversion from cytotoxic to a more immunoregulatory phenotype similar to decidual NK cells. 30,38 In the current study, we found that NK cells downregulated their CD16 expression upon exposure to ovarian tumor microenvironment but this conversion was mitigated by PD-L1 blockade. PD-L1 blockade also resulted in higher amounts of CD57 + NK cells, a subpopulation that have been reported to have a higher cytotoxic capacity with greater responsiveness via CD16 engagement and its presence correlated with better outcomes in squamous cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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The role of transforming growth factor‐beta in immune suppression and chronic inflammation of squamous cell carcinomas

Strait

Wang

2020

Molecular Carcinogenesis

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Despite a decline in the incidence of squamous cell carcinomas (SCCs) over the past 20 years, their survival rate has remained nearly the same, indicating that treatment options have not improved relative to other cancer types. Immunotherapies have a high potential for a sustained effect in SCC patients, but their response rate is low.Here, we review the suppressive role of transforming growth factor-beta (TGFβ) on the antitumor immune response in SCC and present its potential as a therapeutic target in combination with the current range of immunotherapies available for SCC patients. We conclude that SCCs are an optimal cancer type to study the effectiveness of TGFβ inhibition due to the prevalence of dysregulated TGFβ signaling in them. K E Y W O R D S head and neck squamous cell carcinoma, immune checkpoint blockade, immunotherapy, tumor microenvironment 1 | INTRODUCTION Squamous cell carcinomas (SCCs) are cancers that arise from areas of stratified epithelium and are primarily found in the skin, lung, and the epithelial lining of the oropharyngeal and nasopharyngeal cavities.Although skin SCC incidence cannot be estimated because most cancer registries do not collect data on it, deaths associated with nonmelanoma skin cancer, which is primarily SCC, exceed melanoma deaths due to the high number of SCC cases. 1 Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and accounts for 53,000 new cases each year in the United States. 2 Although its incidence has decreased slightly, its mortality rate has slightly increased since 2012, 2 indicating that current therapeutic options for patients with HNSCC have stagnated and novel therapeutics have not yet improved the majority of patient outcomes. The current standard of care is a combination of radiotherapy, surgery, and chemotherapy; patients who do not respond to those typically have incurable recurring metastatic disease. The primary causes of HNSCC are either HPV or heavy tobacco and alcohol use. HPV -HNSCCs are associated with worse prognoses and a less inflammatory immune microenvironment. 3It is long established that mutagen-induced SCC results in elevated levels of secreted transforming growth factor-beta (TGFβ) in the tumor microenvironment. 4 The TGFβ signaling pathway has been reviewed in depth elsewhere, 5,6 and is summarized here in Figure 1.Briefly, when the TGFβ receptor complex binds TGFβ ligand, it phosphorylates receptor-associated Smad2 and Smad3 proteins. Smad2 and Smad3 form a complex with Smad4, which translocates to the nucleus, binds to Smad binding elements on genetic loci, and regulates numerous transcriptional pathways. The TGFβ receptor complex also activates numerous noncanonical signaling pathways independently of Smad proteins. In tobacco and alcohol-associated cases, HNSCC is often preceded by dysregulation of TGFβ signaling, resulting in elevated levels of TGFβ within a tumor while tumor cells Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; HNSCC, head and neck squamous ...

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NK cell dysfunction with down-regulated CD16 and up-regulated CD56 molecules in patients with esophageal squamous cell carcinoma

Cited by 39 publications

References 25 publications

Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer

Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer

PD-L1 blockade enhances anti-tumor efficacy of NK cells

The role of transforming growth factor‐beta in immune suppression and chronic inflammation of squamous cell carcinomas

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