MAX transcriptionally enhances PD-L1 to inhibit CD8+ T cell-mediated killing of lung adenocarcinoma cells

Lung cancer is one of the most common malignancies worldwide and poses a serious threat to human health. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers, while lung adenocarcinoma (LUAD) is the most common pathological type of NSCLC[1]. In the last decade, immune checkpoint blockade (ICB) therapy, such as monoclonal antibodies against programmed cell death protein-1 (PD-1) or its ligand PD-L1, has been approved by the FDA for the treatment of lung cancer[2]. While anti-PD-1/PD-L1 therapy has become a major breakthrough, its effectiveness in NSCLC is as low as 20–30%[3], [4]. The high expression of PD-L1 in tumor cells is a key reason why they evade immune surveillance [5]. Therefore, elucidation of the molecular mechanisms regulating PD-L1 expression speaks promise to provide potential combination therapeutic targets for ICB therapy.

It has been reported that PD-L1 expression can be induced by a variety of exogenous signals, including IFN-γ, EGF, interleukins and TNF-α[6], [7]. Meanwhile, signaling pathways such as JAK/STAT1/IRF1, PI3K/AKT/mTOR, NF-κB and JAK/STAT3 in the tumor microenvironment (TME) have also been shown to indirectly regulate PD-L1 transcription[8]. In addition, intrinsic signaling within tumor cells can also promote PD-L1 transcription. For instance, transcription factors such as AP-1 in Hodgkin's lymphoma, HIF-2α in renal cell carcinoma, and NPM1 in triple-negative breast cancer can promote PD-L1 expression[9], [10], [11]. In NSCLC, high mRNA levels and protein expression of PD-L1 are associated with activation of KRAS, EGFR and ALK and loss of PTEN[8], [12]. In addition, activation of mTOR, MAPK and Myc also enhanced PD-L1 expression in NSCLC[8]. Even so, the underlying mechanisms mediating the regulation of PD-L1 in LUAD are still not well understood.

The oncogene Myc is a key signal driving the progression of many tumors, including LUAD [13]. Myc has been shown to activate PD-L1 expression by directly binding to the PD-L1 promoter in human and murine tumor cells[14]. In addition, high expression of Myc is associated with high PD-L1 expression in tumors and poor patient prognosis[15], [16]. Thus, inhibition of Myc or its upstream signaling has been shown to decrease PD-L1 expression in tumor cells and enhance the therapeutic effect of anti-PD-1 antibodies[17], [18]. During the transcriptional regulation, Myc usually forms a heterodimer with MYC-associated X-factor (MAX)[19]. The bHLHZip protein MAX acts as a cofactor for DNA binding by various members of a network of transcription factors, including the MYC family of oncoproteins and a group of putative MYC antagonists[20]. Although MAX is considered as a context-specific tumor suppressor in small cell lung cancer (SCLC)[21], [22], its role in LUAD is unclear. Based on the above evidence, we hypothesized that MAX may also be associated with the transcription of PD-L1.

In this study, we investigated the potential role of MAX in regulating the transcription of PD-L1 in LUAD cells by analyzing the chromatin immunoprecipitation sequencing (ChIP-seq) data of MAX based on lung cancer cell lines followed by several molecular biology experiments. In addition, we determined that the MAX/PD-L1 axis is associated with CD8+ T cell-mediated killing of LUAD cells and poor outcomes in patients with LUAD.

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