Abstract
Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens.
Highlights
Programmed cell death protein-1 (PD-1), a member of the CD28 family of proteins, is mainly expressed on T-cell surface [1] and its ligand, programmed cell death ligand-1 (PD-L1), is frequently overexpressed in many types of human cancers, including non-small-cell lung cancer (NSCLC), and is associated with a poor prognosis [2]
The aim of the present study was to evaluate the effects of standard chemotherapeutic drugs on the modulation of PD-L1 expression in non-squamous EGFR and ALK wild-type NSCLC cell lines
We evaluated the effect of pemetrexed at different exposure times and concentrations on PD-L1 expression in A549 cells
Summary
Programmed cell death protein-1 (PD-1), a member of the CD28 family of proteins, is mainly expressed on T-cell surface [1] and its ligand, programmed cell death ligand-1 (PD-L1), is frequently overexpressed in many types of human cancers, including non-small-cell lung cancer (NSCLC), and is associated with a poor prognosis [2]. PD-1/PD-L1 axis is a key immune checkpoint pathway that provides inhibitory signals to the immune system in order to modulate the activity of T cells and, plays a crucial role in cancer progression by altering the status of immune surveillance. The engagement of PD-1 by PD-L1 induces an inhibitory signal resulting in the reduction of T-cell proliferation and cytotoxic activity. Immune checkpoint inhibitors have revolutionized the medical treatment approach for metastatic NSCLC patients without oncogenic druggable alterations. The combination of these agents with chemotherapy, both in non-squamous [4] and squamous [5] histologies, has resulted in a significant overall survival (OS) benefit in comparison to standard chemotherapy. The results of the Keynote-189 [4] phase III clinical trial showed that pembrolizumab added to platinum-pemetrexed doublet led to a 50% mortality reduction when compared with chemotherapy alone
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