Background Chemoradiotherapy‐induced PD‐L1 upregulation leads to therapeutic resistance and treatment failure. The PD‐1/PD‐L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD‐1 and PD‐L1 binding without affecting the oncogenic function of intracellular PD‐L1. Reversing the chemoradiation‐induced PD‐L1 expression could provide a new strategy to achieve a greater anti‐tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti‐tumour immunity of chemoradiotherapy by decreasing treatment‐induced PD‐L1 expression in non‐small cell lung cancer (NSCLC). Methods A drug array was used to recognize compounds that can suppress the cisplatin‐induced and radiation‐induced PD‐L1 expression in NSCLC via the flow cytometry‐based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation‐induced PD‐L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo. Results BRD4 inhibitors JQ1 and ARV‐771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD‐L1 expression by disrupting the recruitment of BRD4‐IRF1 complex to PD‐L1 promoter. A positive correlation between BRD4 and PD‐L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD‐1 blockade to show a robust anti‐tumour immunity dependent on CD8+ T cell through limiting chemoradiation‐induced tumour cell surface PD‐L1 upregulation in vivo. Notably, the BRD4‐targeted combinatory treatments did not show increased toxicities. Conclusion The data showed that BRD4‐targeted therapy synergized with chemoradiotherapy and anti‐PD‐1 antibody by boosting anti‐tumour immunity in NSCLC.
Metastasis remains the primary cause of small cell lung cancer (SCLC)-related deaths. Growing evidence links tumor metastasis with a pre-metastatic microenvironment characterized by an anti-inflammatory response, immunosuppression, and the presence of tumor-derived exosomes. To clarify the relationships among these factors in SCLC, we analyzed SCLC patient samples as well as a mouse model. Among the infiltrating immune cells, our study focused on the tumor-associated macrophages (TAMs), that are well-known to promote tumor progression and metastasis. We found that high expression of the alternatively activated (M2) TAM marker, CD206+ was associated clinically with a poorer prognosis and metastasis state in patients with SCLC. Moreover, infiltrating macrophages (MØ) were found in the metastatic foci of an SCLC mouse model. Additionally, we observed dominant switching to M2 phenotype, accompanied by increased NLRP6 expression. Since tumor-derived exosomes are the key links between the tumor and its immune microenvironment, we further investigated whether SCLC-derived exosomes contributed to the MØ phenotype switch. Our findings showed for the first time that SCLC-derived exosomes induce the M2 switch via the NLRP6/NF-κB pathway, and thus, promote SCLC metastasis in vitro and in vivo. Collectively, these results indicate a novel mechanism by which SCLC-derived exosomes induce immunosuppression of distant MØ to promote systemic metastasis by activating NLRP6. Here, we highlight the close relationship between the tumor-derived exosomes, inflammasomes and immune microenvironment in SCLC metastasis.
The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
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