Antitumor activity of dual blockade of PD-L1 and MEK in NSCLC patients derived three-dimensional spheroid cultures

Journal of Experimental & Clinical Cancer Research

Marianna Abate¹  Amalia Luce¹  Silvia Zappavigna¹  Michele Caraglia¹  Mario Santini²  Alfonso Fiorelli²  Giovanni Vicidomini²  Floriana Morgillo³  Vincenza Ciaramella³  Erika Martinelli³  Fortunato Ciardiello³  Carminia Maria Della Corte³  Teresa Troiani³  Raimondo Di Liello³  Giusi Barra³ 

[1] Biochimica Generale, Dipartimento di Medicina di Precisione, Università degli studi della Campania “Luigi Vanvitelli”;Chirurgia Toracica, Dipartimento di Scienze Mediche Traslazionali, Università degli studi della Campania “Luigi Vanvitelli”;Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli studi della Campania “Luigi Vanvitelli”;

关键词: MEK;    PD-L1;    Lung cancer;    Organoid cultures;   

DOI  :  10.1186/s13046-019-1257-1

来源: DOAJ

【 摘 要 】

Abstract Background Anti-PD-1/PD-L1 drugs are effective as monotherapy in a proportion of NSCLC patients and there is a strong rationale for combining them with targeted therapy. Inhibition of MAPK pathway may have pleiotropic effects on the microenvironment. This work investigates the efficacy of combining MEK and PD-L1 inhibition in pre-clinical and ex-vivo NSCLC models. Methods We studied the effects of MEK inhibitors (MEK-I) on PD-L1 and MCH-I protein expression and cytokine production in vitro in NSCLC cell lines and in PBMCs from healthy donors and NSCLC patients, the efficacy of combining MEK-I with anti-PD-L1 antibody in ex-vivo human spheroid cultures obtained from fresh biopsies from NSCLC patients in terms of cell growth arrest, cytokine production and T-cell activation by flow cytometry. Results MEK-I modulates in–vitro the immune micro-environment through a transcriptionally decrease of PD-L1 expression, enhance of MHC-I expression on tumor cells, increase of the production of several cytokines, like IFNγ, IL-6, IL-1β and TNFα. These effects trigger a more permissive anti-tumor immune reaction, recruiting immune cells to the tumor sites. We confirmed these data on ex-vivo human spheroids, showing a synergism of MEK and PD-L1 inhibition as result of both direct cancer cell toxicity of MEK-I and its immune-stimulatory effect on cytokine secretion profile of cancer cells and PBMCs with the induction of the ones that sustain an immune-reactive and inflammatory micro-environment. Conclusions Our work shows the biological rationale for combining immunotherapy with MEK-I in a reproducible ex-vivo 3D-culture model, useful to predict sensitivity of patients to such therapies.

【 授权许可】

Unknown