Synergistic effects of nab-PTX and anti-PD-1 antibody combination against lung cancer by regulating the Pi3K/AKT pathway through the Serpinc1 gene

Abstract

Lung cancer is a type of cancer with higher morbidity and mortality. In spite of the impressive response rates of nab-paclitaxel (nab-PTX) or programmed cell death-1 (PD-1) and its ligand inhibitors, the effective treatment remains limited. Currently, alternative strategies aim at drug combination of nab-PTX and PD-1/PD-L1 inhibitors. Even as the clinical impact of the combined agents continues to increase, basic research studies are still limited and the mechanisms underlying this synergy are not well studied. In this study, we evaluated the antitumor efficacy and the molecular mechanisms of action of nab-PTX in combination with anti-PD-1 antibody, using Lewis lung carcinoma (LLC) cell and subcutaneously transplanted tumor models. The combination of nab-PTX and anti-PD-1 antibody displayed stronger antitumor effects, manifested at tumor volume, proliferation and apoptosis through Ki67 and TUNEL staining. In-vivo experiments showed significant increases in CD4+ T cells, CD8+ T cells, IFN-γ, TNF-α, IL-2, PF, and Gzms-B, exerting antitumor effects with reductions in MDSCs and IL-10 after the treatments. Furthermore, transcriptomic analysis indicated 20 overlapped differentially expressed genes, and Serpin peptidase inhibitor clade C Member 1 (Serpinc1) was downregulated during treatment in vivo, whose expression level was markedly related to metastasis and overall survival of lung cancer patients. Functional enrichment analysis of the target gene revealed primary GO terms related to tumor, which warrants further investigation. We also found that Serpinc1 overexpression promoted cell proliferation, migration, and invasion and inhibited cell apoptosis of LLC cells in vitro, possibly regulating the associated factors via the Pi3K/AKT pathway. In summary, our results reveal the synergistic antitumor responses of nab-PTX combined with anti-PD-1 antibody, in which Serpinc1 may play an important role, providing a target gene for combination treatment strategy.

Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial

“…Nab-paclitaxel has been shown effective as a first-line treatment 28 and demonstrated longer progression-free survival than paclitaxel in first-line treatment for advanced gastric cancer 30 . Third, nab-paclitaxel has a synergistic effect with immunotherapy 61 , 62 . In addition, nab-paclitaxel has a synergistic effect with radiotherapy in lung cancer, pancreatic cancer, and head and neck squamous cancer, among others 43 , 63 – 65 .…”

Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations

“…In the PARAMOUNT study [39], patients who had maintenance Pemetrexed had an mOS of 13.9 months, and a later systematic review of the clinical trial population [40] showed that patients with EGFR mutations (without untreated brain metastases) who received Pemetrexed-containing regimens after TKI exhaustion had a weighted mOS of 15.91 months. Therefore, most novel chemo-immunotherapy studies chose to disregard the possible immunotherapy-potentiating effect of Paclitaxel [41][42][43] in favour of the possible cytotoxic advantage of Pemetrexed chemotherapy. IMpower151 [35] claimed to use the original ABCP regimen, but 97.4% of patients received Pemetrexed instead of Paclitaxel, although, in contraposition with the other studies, it included Bevacizumab in both arms and enrolled patients with EGFR and ALK genomic alterations (as well as patients without actionable mutations).…”

Efficiency and toxicity of nab-paclitaxel and camrelizumab in the second or above line treatment of advanced non-small cell lung cancer: a retrospective cohort study

“…We further found that the synergistic mechanism of this regimen may lie in depleting Treg ratio to activate an immune response. However, due to the limitations of sample size, retrospective and single-center design of this study, many problems need to be resolved, such as the exact molecular mechanism ( 20 ), further optimization of the regimen, screening for the priority population, elucidating resistance mechanism ( 40 ), and so on. With the rapid development and accumulation of clinical experience of IO application, these puzzles will be gradually resolved and more and more patients will be able to benefit from this regimen.…”

“…Correspondingly, considering the higher penetrance capacity relative to docetaxel or paclitaxel, nabptx would probably be a more suitable partner for the combination of PD-1/PD-L1 inhibitors (11). Accumulating evidence has shown that the drug combination of nab-ptx and PD-1/PD-L1 inhibitors in solid tumors exerts obvious synergistic effect with lower toxicities (16)(17)(18)(19), although the mechanism remains unknown (20). With regard to PD-1/ PD-L1 inhibitors, in China, camrelizumab was the first PD-1/PD-L1 antibody to be approved by the National Medical Products Administration (NMPA) in 2019 for the first-line treatment of advanced NSCLC (21,22).…”