Adaptive NK Cell Therapy Modulated by Anti-PD-1 Antibody in Gastric Cancer Model

Abstract

Recently, adaptive NK cell therapy has become a promising treatment but has limited efficacy as a monotherapy. The identification of immune checkpoint inhibitor (ICI) molecules has opened a new horizon of immunotherapy. Herein, we aimed to demonstrate the cytotoxic effects of a polytherapy consisting of ex vivo expanded IL-2-activated NK cells combined with human anti-PD-1 antibody as an important checkpoint molecule in a xenograft gastric cancer mouse model. EBV-LCL cell is used as a feeder to promote NK cell proliferation with a purity of 93.4%. Mice (NOG, female, 6–8 weeks old) with xenograft gastric tumors were treated with PBS, ex vivo IL-2-activated NK cells, IL-2-activated NK cell along with human anti-PD-1 (Nivolumab), and IL-2-activated pretreated NK cells with anti-PD-1 antibody. The cytotoxicity of ex vivo expanded NK cells against MKN-45 cells was assessed by a lactate dehydrogenase (LDH) assay. Tumor volume was evaluated for morphometric properties, and tumor-infiltrating NK cells were assessed by immunohistochemistry (IHC) and quantified by flow cytometry. Pathologic responses were considered by H and E staining. Ex vivo LDH evaluation showed the cytotoxic potential of treated NK cells against gastric cancer cell line. We indicated that the adoptive transfer of ex vivo IL-2-activated NK cells combined with anti-PD-1 resulted in tumor growth inhibition in a xenograft gastric cancer model. Mitotic count was significantly decreased (*p < 0.05), and the tumor was associated with improved infiltration of NK cells in the NK-anti-PD-1 pretreated group (*p < 0.05). In conclusion, the combination approach of activated NK cells and anti-PD-1 therapy results in tumor growth inhibition, accompanied by tumor immune cell infiltration in the gastric tumor model.

MAGEA11 as a STAD Prognostic Biomarker Associated with Immune Infiltration

“…Circulating CD4+ T cells can target cancer cell surface antigens and activate peripheral blood CD8+ T cells, allowing them to enter the tumor microenvironment and kill cancer cells [ 63 , 64 ]. Bihui et al confirmed that NK cells have strong antitumor activity and can effectively eliminate and inhibit gastric cancer cells [ 65 , 66 ]. Our data indicated that with high expression of MAGEA11 , the immune microenvironment inhibits the infiltration of immune cells, creating an environment for immune escape tolerance.…”

Contribution of natural killer cells in innate immunity against colorectal cancer

“…Following preclinical research, the synergy potential of targeted antibodies with NK cell therapy should be further investigated in clinical trials. Our research group demonstrated that pretreated checkpoint blockade NK cells could effectively enhance the NK cells’ trafficking in TME and beneficially reduce the tumor cell mitosis in gastric cancer xenograft model ( 189 ). However the same results was not achieved in chemo immune cell therapy of Intratumoral injection of NK cells in combination with capecitabine in gastric cancer xenograft model in the other study of our group ( 190 ).…”

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

“…In addition, the cytokines can activate NK cells and promote their proliferation to enhance anti-tumor activity, such as IL-2, IL-12, IL-15, and IL-18 ( 186 – 188 ). NK cells activated by IL-2 which combined with anti–PD-1 can inhibit tumor growth in xenograft GC models ( 189 ). In addition, IL-15 can increase the infiltration of NK cells in the tumor ( 190 ) and improve the survival rate in the treatment of GC liver metastasis–bearing mice ( 191 ).…”