PLIN3 knockdown enhances T cell-mediated cytotoxicity in non-small cell lung cancer via autophagy-dependent PD-L1 degradation.
TL;DR
It is shown that targeting PLIN3 can induce autophagy, which promotes the degradation of PD-L1, ultimately leading to enhanced activation of T cells and an innovative approach to enhance the efficacy of immunotherapy in lung cancer.
Abstract
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.