BACKGROUND
Recently, immune checkpoint inhibitors (ICIs), especially those that targets PD-1/PD-L1, have significantly altered the treatment approach for NSCLC. Nevertheless, many patients experience different levels of resistance after receiving treatment with ICIs, which restrict their broader use in clinical practice. Therefore, to enhance the overall efficacy of ICIs, there is an immediate necessity to further explain the processes of immune evasion in NSCLC, especially the modulatory mechanism of PD-L1.
METHODS
IHC was used to evaluate the protein expression level of PLIN3 and PD-L1 in NSCLC tissues. The impact of PLIN3 on PD-L1 was analyzed in NCI-H1975 and NCI-H157 cells using western blot, flow cytometry and quantitative PCR (qPCR). Immunofluorescence was performed to examine the effect of PLIN3 on the autophagy level. The levels of Granzyme B (GZMB) and interferon-gamma (IFN-γ) secreted by T cell were assessed. Bioinformatic analyses, including immune infiltration estimation and TIDE score, were performed using TCGA data.
RESULTS
In this research, we discovered that elevated PLIN3 level was linked to decreased infiltration of CD4+ and CD8+ T cell, a higher TIDE score, and poorer immunotherapy response. In NSCLC tissues, there was a positive correlation between PLIN3 and PD-L1. Besides, the level of PLIN3 protein is significantly reduced in patients who achieve pathological complete response. In addition, PLIN3 knockdown markedly reduced the level of PD-L1 protein. Mechanistically, PLIN3 knockdown activated autophagy, and promoted PD-L1 degradation via the autophagic-lysosomal pathway, which consequently shortened its protein half-life. Furthermore, PLIN3 knockdown enhanced T-cell-mediated tumor killing and resulted in an increased secretion of the effector molecules, including granzyme B and IFN-γ.
CONCLUSIONS
In summary, our study has shown that targeting PLIN3 can induce autophagy, which promotes the degradation of PD-L1, ultimately leading to enhanced activation of T cells. This research is the first to investigate the function of PLIN3 in the immune microenvironment, revealing its critical function in immune evasion and highlighting its promise as a treatment target. This offers an innovative approach to enhance the efficacy of immunotherapy in lung cancer.
Hanqiong Zhou, Songqing Fan, Ouyang Min et al.· International Immunopharmaco...· 0 citations
Abstract Background Nasopharyngeal carcinoma (NPC) is considered a typical “hot” tumor, yet its immune evasion mechanisms remain poorly defined, and immunotherapy efficacy is suboptimal. Attenuation of intrinsic tumor cell immunogenicity to evade T cell recognition and cytotoxicity represents a major route of tumor immune evasion, whose mechanistic basis is largely unelucidated. Methods Multiplex immunofluorescence and immunohistochemistry were used to assess correlations between mitochondrial leucyl-transfer RNA synthetase 2 (LARS2) expression, CD8+ T cell infiltration and immunotherapy response in NPC tissues. In vitro CD8+ T cell co-cultures, immunodeficient nude mice and immunocompetent murine models were used to explore LARS2-dependent CD8+-mediated antitumor immunity. Blue native polyacrylamide gel electrophoresis (BN-PAGE), extracellular flux and other mitochondrial functional assays were performed to characterize the roles of LARS2 and leucine in electron transport chain (ETC) translation and oxidative phosphorylation (OXPHOS) activity. Chromatin immunoprecipitation-quantitative PCR, ELISA and flow cytometry analyzed epigenetic modifications, major histocompatibility complex class I (MHC-I) expression and antigen presentation. Leucine supplementation combined with anti-programmed cell death protein-1 (PD-1) therapy was tested in mouse models to evaluate in vivo therapeutic efficacy against NPC immune escape. Results We demonstrated that LARS2, a gene mapped to the 3p21 chromosomal region, was significantly downregulated in NPC, and its expression is positively correlated with patient prognosis and response to immunotherapy. Through in vitro and in vivo experiments, we demonstrated that restoration of LARS2 expression accelerates the translation of mitochondrial ETC subunits, enhances OXPHOS, and upregulates MHC-I expression via an epigenetic mechanism. These effects work together to enhance tumor antigen presentation and augment CD8+ T cell-mediated cytotoxicity. Furthermore, we demonstrated that a high-leucine diet increases LARS2 expression and improves the effectiveness of anti-PD-1 immunotherapy. Conclusions This study uncovers a novel mechanism by which the tumor suppressor LARS2 inhibits immune evasion in NPC through upregulation of MHC-I, and highlights a high-leucine diet as a promising strategy to sensitize tumors to immunotherapy.
Mei Yang, Yongzhen Mo, Daixi Ren et al.· Journal for ImmunoTherapy of...· 0 citations