The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15009-e15009
Author(s):  
Md Mohiuddin ◽  
Hideharu Kimura ◽  
Satoshi Watanabe ◽  
Miki Abo ◽  
Takashi Sone ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nk Cells ◽  
Nk Cell ◽  
Inhibitory Effect ◽  
Small Cell ◽  
Inhibitory Effects ◽  
Small Cell Lung ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
And Function

e15009 Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.

scholarly journals 710 Differences in the susceptibility of human small cell lung cancer variants to NK cell-mediated lysis can be overcome with the addition of N803 (IL-15 superagonist)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A739-A739
Author(s):  
Kristen Fousek ◽  
Lucas Horn ◽  
Haiyan Qin ◽  
Bobby Reddy ◽  
Lennie Sender ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Nk Cells ◽  
Cell Lung Cancer ◽  
Nk Cell ◽  
Xenograft Model ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Cell Phenotype ◽  
Small Cell Lung

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive tumor with a 5-year survival rate of less than 5%. Traditionally characterized as a neuroendocrine (NE) cancer, several subtypes have now been identified which vary in their phenotypic and transcriptional profiles. Classical NE tumors are molecularly defined as ASCL1+ or NEUROD1+ and exhibit an epithelial phenotype, expressing cytokeratin and E-cadherin (E-Cad). In contrast, non-classical variants express POU2F3 or YAP1 and are enriched in mesenchymal features, such as high levels of vimentin (Vim). Prior studies describe that non-NE variants of SCLC are less susceptible to chemotherapy and may arise via therapeutic selection. With the addition of immune checkpoint blockade to first-line chemotherapy for the treatment of advanced SCLC, understanding whether SCLC variants respond differently to immunotherapy is crucial.MethodsWe utilized a range of pre-clinical models to investigate whether molecular and phenotypic variants of SCLC differ in their susceptibility to immune-mediated lysis. Following extensive characterization at the RNA and protein levels for expression of ASCL1, NEUROD1, POU2F3, YAP1, epithelial E-Cad, mesenchymal Vim, and other markers of cell phenotype, a panel of cells including each variant subtype were selected for further study.ResultsUpon exposure to healthy donor effector NK cells, the more epithelial cells were highly susceptible to NK-mediated cytotoxicity while all mesenchymal SCLC cells remained highly refractory to NK-mediated lysis. This prompted us to investigate immunotherapy approaches such as the addition of N803, a mutant IL-15 superagonist, to improve the activation and proliferation of NK cells. In a xenograft model utilizing the mesenchymal YAP1+ H841 cell line subcutaneously implanted into nude mice devoid of all immune cells except for NK cells, we observed that the weekly administration of N803 resulted in a significant increase in the number of activated NK cells within the spleens of treated mice. Additionally, NK cells from treated mice produced significantly higher levels of IFN-gamma and granzyme B, resulting in a significant decrease in overall tumor burden.ConclusionsOur data indicates that N803-activated NK cells effectively mediate lysis of SCLC across all variant types, including those previously completely refractory to traditional NK cell lysis. These results highlight the potential of N803 as a novel immune-based intervention for the treatment of all variants of SCLC.Ethics ApprovalPBMCs were obtained from healthy donors at the NIH Clinical Center Blood Bank (NCT00001846). All animal studies were approved and conducted in accordance with an IACUC-approved animal protocol (LTIB-57) with the approval the NIH/NCI Institutional Animal Care and Use Committee.

Natural killer cells and their activity as a potential biomarker for predicting response to checkpoint inhibitors in non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15559-e15559
Author(s):  
Paul Y. Song ◽  
Yong-Hee Cho ◽  
Myeong Geun Choi ◽  
Dong Ha Kim ◽  
Yun Jung Choi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nk Cell Activity

e15559 Background: Despite the increased promise of checkpoint inhibitors in the treatment of non-small cell lung cancer, the majority of patients do not respond and the potential for severe toxicity is significant. Unfortunately, the predictive value of PD-L1 expression has not always proven to be definitive and the overall need to find better biomarkers that will optimize the selection of patients who will best respond to therapy remains. Recent evidence has pointed to Natural Killer (NK) cells as an essential mediator in overall response to checkpoint inhibitors. We explore whether NK cell populations and/or their activity have any correlation with response. Methods: Peripheral blood mononuclear cells (PBMCs) from nine patients with Stage IV non-small cell lung cancer (four adenocarcinoma, five squamous cell carcinoma) were collected pre and post six-weeks of checkpoint immunotherapy (six received pembrolizumab, and three received nivolumab). Overall, four of nine (44.5%) were diagnosed as SD or PR via RECIST 1.1. The immune cell composition of the PBMCs of all nine patients was analyzed using multi-variated single-cell analysis using mass cytometry (CyTOF) with an optimized 32-marker panel. Natural Killer (NK) cell activity was measured with the NKVue kit which detects NK-secreted IFN-γ levels using a quantitative sandwich ELISA from NK cells exposed to a specific recombinant cytokine. Results: The overall percentages of NK cell populations found in the immune cells of PBMCs were prominently elevated in patients who responded (SD or PR) to checkpoint therapy compared to those who had progressive disease (non-responders). While there were no significant differences in the population of other immune cells between these two groups, the overall NK cell activity in patients who responded was highly elevated compared to the NK cell activity in non-responders. From the analysis of NK subsets, there were no differences in the population of early NK cells between the two groups, but the functionally differentiated late NK cells were prominently high in the responder group. Conclusions: Natural Killer (NK) cells have been recently implicated to play a key role in anti-tumor response to checkpoint inhibitors and our results suggest that the overall number of NK cells and their activity could prove to be an independent and reliable predictive tool/biomarker in patients with NSCLC.

scholarly journals Growth inhibitory effects of miR‐221 and miR‐222 in non‐small cell lung cancer cells

2015 ◽  
Vol 4 (4) ◽  
pp. 551-564 ◽  
Author(s):  
Ryo Yamashita ◽  
Mitsuo Sato ◽  
Tomohiko Kakumu ◽  
Tetsunari Hase ◽  
Naoyuki Yogo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Inhibitory Effects ◽  
Small Cell Lung ◽  
Growth Inhibitory
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