USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade

Abstract

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.

Gene Coexpression Network Characterizing Microenvironmental Heterogeneity and Intercellular Communication in Pancreatic Ductal Adenocarcinoma: Implications of Prognostic Significance and Therapeutic Target

“…Therefore, it is reasonable for us to assume that the hub genes of these two networks are responsible for the clinical behaviors of PDAC. Because the majority of hub genes could be traced back to tumor cells ( Figure 2C ), our findings reinforce the notion that intrinsic tumor genes shape the microenvironment and regulate tumor development and therapeutic responses ( 42 – 44 ).…”

Protein Phosphatase PPM1B Inhibits Gastric Cancer Progression and Serves as a Favorable Prognostic Biomarker

“…Our data showed that the phosphorylation level of p65-NF-κB on Serine536 residue was downregulated upon PPM1B overexpression. Consistently, Yang et al’s16 study as well as Sun et al’s18 data both showed that PPM1B participates in regulating NF-κB signaling pathways. In contrast, PPM1B protein expression can be directly targeted and inhibited by miR-186 in bladder cancer, thus affecting the G1/S phase transition of cell cycle 9.…”

“…According to Miller and colleagues’ study, PPM1B depletion significantly sensitized U2OS cells to bleomycin-induced cell death at a minimal effective concentration 14. Moreover, USP12 downregulation can orchestrate a protumorigenic microenvironment and enhance lung tumor resistance to PD-1 blockade,16 thus highlighting the potential of PPM1B as a novel therapeutic target for malignancies. Besides antitumor agents, PPM1B can also modulate the inflammatory effects of berberine in HepG2 cells17 as well as the necroptosis effects of 3-bromopyruvate in MDA-MB-231 cells 5…”

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

“…It has been reported that mutant KRAS can remodel the TME by regulating the production and secretion of pro-or antiinflammatory cytokines and chemokines [38] . The oncogenic mutant KRAS represses the expression of interferon regulatory factor 2 (IRF2) and results in increased production of C-X-C motif chemokine ligand 3 (CXCL3), which binds to C-X-C motif chemokine receptor 2 (CXCR2) on myeloid-derived suppressor cells (MDSCs) and subsequently recruits the MDSCs to impede the cytotoxic T cells [39] . In lung cancer, the ubiquitin-specific protease 12 (USP12) induces protein phosphatase 1B, which thwarts transcription factor P65 (NF-κB).…”

“…, which can result in an immunosuppressive TME through recruiting the M2 macrophages, inducing PD-L1 expression and blocking the responses to T cells. Oncogenic mutant KRAS inhibits USP12 and further promotes the production of chemokines through NF-κB, which ultimately causes the resistance to anti-PD-1 [ 40 ] . Additionally, it has been reported that the development of resistance to anti-PD-L1 and MEK inhibition is the result of increasing IL-17 and IL-22 secreted by accumulated infiltration of Th17 in KRAS mut /TP53 -/- co-mutant lung cancer patients [ 41 ] .…”