Tumor cell lysis and synergistically enhanced antibody-dependent cell-mediated cytotoxicity by NKG2D engagement with a bispecific immunoligand targeting the HER2 antigen

BackgroundThe poor clinical accuracy to predict the survival of colon cancer patients is associated with a high incidence rate and a poor 3-year survival rate. This study aimed to identify the poor prognostic biomarkers of colon cancer from natural killer cell-mediated cytotoxic pathway (NKCP), and establish a logistical regression scoring model to predict its prognosis.MethodsBased on the expressions and methylations of NKCP-related genes (NRGs) and the clinical information, dimensionality reduction screening was performed to establish a logistic regression scoring model to predict survival and prognosis. Risk score, clinical stage, and ULBP2 were used to establish a logistic regression scoring model to classify the 3-year survival period and compare with each other. Comparison of survival, tumor mutation burden (TMB), estimation of immune invasion, and prediction of chemotherapeutic drug IC50 were performed between low- and high-risk score groups.ResultsThis study found that ULBP2 was significantly overexpressed in colon cancer tissues and colon cancer cell lines. The logistic regression scoring model was established to include six statistically significant features: S = 1.70 × stage – 9.32 × cg06543087 + 6.19 × cg25848557 + 1.29 × IFNA1 + 0.048 × age + 4.37 × cg21370856 − 8.93, which was used to calculate risk score of each sample. The risk scores, clinical stage, and ULBP2 were classified into three-year survival, the 3-year prediction accuracy based on 10-fold cross-validation was 80.17%, 67.24, and 59.48%, respectively. The survival time of low-risk score group was better than that of the high-risk score group. Moreover, compared to high-risk score group, low-risk score group had lower TMB [2.20/MB (log10) vs. 2.34/MB (log10)], higher infiltration score of M0 macrophages (0.17 vs. 0.14), and lower mean IC50 value of oxaliplatin (3.65 vs 3.78) (p < 0.05).ConclusionsThe significantly upregulated ULBP2 was a poor prognostic biomarker of colon cancer. The risk score based on the six-feature logistic regression model can effectively predict the 3-year survival time. High-risk score group demonstrated a poorer prognosis, higher TMB, lower M0 macrophage infiltration score, and higher IC50 value of oxaliplatin. The six-feature logistic scoring model has certain clinical significance in colon cancer.

Section: Discussionmentioning

confidence: 99%

Significance of logistic regression scoring model based on natural killer cell-mediated cytotoxic pathway in the diagnosis of colon cancer

Zhang²,

Ji³

et al. 2023

“…One example of the importance of immunoligands to enhance mAbs-mediated ADCC is the development of immunoligands fusing the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80, DNAM-1 and NKG2D to a singlechain fragment variable (scFv) targeting HER2 on different solid tumors (171,172). The binding of these immunoligands to HER2 on cancer cells and to NK cell receptors enhanced ADCC mediated by trastuzumab and cetuximab against HER2 positive cancer cells (171, 172) (Table 3).…”

Section: Immunoligandsmentioning

confidence: 99%

Potentiation of natural killer cells to overcome cancer resistance to NK cell-based therapy and to enhance antibody-based immunotherapy

Fantini,

Arlen,

Tsang

2023

Natural killer (NK) cells are cellular components of the innate immune system that can recognize and suppress the proliferation of cancer cells. NK cells can eliminate cancer cells through direct lysis, by secreting perforin and granzymes, or through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves the binding of the Fc gamma receptor IIIa (CD16), present on NK cells, to the constant region of an antibody already bound to cancer cells. Cancer cells use several mechanisms to evade antitumor activity of NK cells, including the accumulation of inhibitory cytokines, recruitment and expansion of immune suppressor cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), modulation of ligands for NK cells receptors. Several strategies have been developed to enhance the antitumor activity of NK cells with the goal of overcoming cancer cells resistance to NK cells. The three main strategies to engineer and boost NK cells cytotoxicity include boosting NK cells with modulatory cytokines, adoptive NK cell therapy, and the employment of engineered NK cells to enhance antibody-based immunotherapy. Although the first two strategies improved the efficacy of NK cell-based therapy, there are still some limitations, including immune-related adverse events, induction of immune-suppressive cells and further cancer resistance to NK cell killing. One strategy to overcome these issues is the combination of monoclonal antibodies (mAbs) that mediate ADCC and engineered NK cells with potentiated anti-cancer activity. The advantage of using mAbs with ADCC activity is that they can activate NK cells, but also favor the accumulation of immune effector cells to the tumor microenvironment (TME). Several clinical trials reported that combining engineered NK cells with mAbs with ADCC activity can result in a superior clinical response compared to mAbs alone. Next generation of clinical trials, employing engineered NK cells with mAbs with higher affinity for CD16 expressed on NK cells, will provide more effective and higher-quality treatments to cancer patients.

Section: Targeted Activation Receptorsmentioning

confidence: 99%

“…In addition, B7-H6:HER2-scFv and AICL:HER2-scFv synergistically enhanced the ADCC of the therapeutic antibodies trastuzumab and cetuximab, respectively. Kellner C constructed bispecific immunoligand UL16 binding protein 2 (ULBP2):HER2-scFvm, which can promote NK cell cytotoxicity against tumors and enhance ADCC in combination with cetuximab ( 59 ). The anti-CD137 agonist urelumab can overcome transforming growth factor (TGF)-β-mediated inhibition of human NK-cell proliferation and anti-tumor function and preserve the expressions of NKG2D, granzyme B, and interferon-gamma (IFN-γ) in HER2-positive primary breast cancer ( 60 ).…”

Section: Regulatory Mechanisms and Research Strategies Of Nk Cells An...mentioning

confidence: 99%

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Liu

2022

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as trastuzumab and pertuzumab, are the cornerstone of adjuvant therapy for HER2-positive breast cancer. A growing body of preclinical and clinical evidence points to the importance of innate immunity mediated by antibody-dependent cellular cytotoxicity (ADCC) in the clinical effect of mAbs on the resulting anti-tumor response. In this review, we provide an overview of the role of natural killer (NK) cells and ADCC in targeted therapy of HER2-positive breast cancer, including the biological functions of NK cells and the role of NK cells and ADCC in anti-HER2 targeted drugs. We then discuss regulatory mechanisms and recent strategies to leverage our knowledge of NK cells and ADCC as an immunotherapy approach for HER2-positive breast cancer.