Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells

by Selleckchem | Apr 24 2023

Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.

Comments：

The study investigated the effect of immune checkpoint inhibitors (ICIs) on the cytotoxic effects of chemotherapy in lung adenocarcinoma cell lines with different PD-L1 expression levels. The results demonstrated that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or cell line used. Durvalumab was found to be the most promising ICI that potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. On the other hand, nivolumab exhibited depotentiating trends in several combinations.

The study employed a resazurin-based assay to evaluate the efficacy of seven chemotherapeutic agents, including cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel, and paclitaxel, in the presence or absence of four ICIs, namely nivolumab, pembrolizumab, atezolizumab, and durvalumab. The study further confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage, as indicated by immunostaining of γH2AX in treated cells. However, this effect was strongly dependent on the chemotherapy agent and cell line used.

The findings of this study suggest that the use of ICIs in combination with chemotherapy can lead to variable outcomes, depending on the specific ICIs and chemotherapy agents used and the PD-L1 expression levels of the tumor. These results have significant implications for developing personalized treatment strategies for patients with NSCLC. Future studies will need to elucidate the underlying mechanisms of the observed ICI-induced potentiation or depotentiation to further optimize the combination therapy approach.