Nintedanib enhances the efficacy of PD-L1 blockade by upregulating MHC-I and PD-L1 expression in tumor cells

Abstract

Background: Immune checkpoint inhibitors (ICIs), such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have been widely applied in clinical and scientific research. Despite their effective antitumor effects in clinical tumor therapy, most tumors are still resistant to ICIs and long-term benefits are lacking. In addition, tumor patients complicated with interstitial lung disease limit the application of ICI therapy. Therefore, for these cases, there is an urgent need to develop new methods to relieve lung complications and enhance the efficacy of ICI therapy. Nintedanib, a potent triple angiokinase inhibitor approved for the treatment of progressive fibrotic interstitial lung disease. However, its immunotherapy synergy properties and mechanism are still pending further exploration. Methods:To explore the therapeutic potential of nintedanib and αPD-L1 combination therapy, MC38, LLC, and 4T1 tumor models were used to investigate antitumor and antimetastatic activities in vivo. An idiopathic pulmonary fibrosis-tumor bearing model was used to evaluate the effect of the synergy therapy on tumor model complicated with lung disease. Moreover, RNA-seq, immunohistochemistry, and flow cytometry were utilized to analyze the effect of combination treatment on the tumor microenvironment. The bioactivity following different treatments was determined by western blotting, CCK-8, and flow cytometry.Results: In this study, nintedanib and αPD-L1 synergy therapy exhibited significant antitumor, antimetastatic and anti-pulmonary fibrosis effects. Both in vitro and in vivo experiments revealed that these effects included promoting vessel normalization, increasing infiltration and activation of immune cells in tumors, enhancing the response of interferon-gamma, and activating the MHC class I-mediated antigen presentation process. Moreover, our results showed an increased expression of PD-L1 and promoted phosphorylation of STAT3 after nintedanib (1 µM) treatment. Conclusion:The combination of nintedanib and αPD-L1 increased ICI therapy responses, relieved lung complications and further activated the tumor immune microenvironment; thus, exhibiting a notable antitumor effect. Accordingly, the nintedanib synergy strategy is expected to be a promising candidate therapy for tumor patients complicated with interstitial lung disease in clinical practice.

Sitagliptin Alleviates Radiation-Induced Intestinal Injury by Activating NRF2-Antioxidant Axis, Mitigating NLRP3 Inf--lammasome Activation, and Reversing Gut Microbiota Disorder

“…The MC38-luc cells (1 × 10 6 ) were subcutaneously injected into the right flank of C57BL/6 mice. Seven days after tumor transplantation (the volume of the tumors reached 250 mm 3 approximately) [ 16 , 17 ], the mice were divided into six groups randomly: Con group, Sitagliptin (20 mg/kg) group, Sitagliptin (100 mg/kg) group, IR group, IR+Sitagliptin (20 mg/kg) group, and IR+Sitagliptin (100 mg/kg) group. All mice were anaesthetized with 1.5% sodium pentobarbital during IR and treated with PBS or different concentrations of Sitagliptin or a single dose of 8 Gy local IR or combination of IR with Sitagliptin.…”

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

“…The specific combination of NCS with an anti-PD-1 mAb points to a more general effect, which is the inhibition of the PD-1/PD-L1 checkpoint signaling via activation of the STAT3 pathway. There are multiple examples of drugs, chemicals, and natural products capable of promoting PD-1 or decreasing PD-L1 expression via a STAT3-dependent action [ 93 , 94 , 95 , 96 , 97 ]. STAT3 is a master regulator of the PD-1/PD-L1 immune checkpoint [ 98 ].…”

Immunologic Gene Sets Reveal Features of the Tumor Immune Microenvironment and Predict Prognosis and Immunotherapy Response: A Pan-Cancer Analysis

“…Anticancer immunotherapy, mainly immune checkpoint inhibitors (ICIs), has emerged as a new pillar in cancer management ( 1 , 2 ). These treatments work by overcoming tumor-induced immunosuppression, thereby achieving immune-mediated tumor clearance ( 3 ).…”