USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy

Abstract

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.

Development and validation of a novel ubiquitination-related gene prognostic signature based on tumor microenvironment for colon cancer

“…It has been suggested that inhibition of USP8 increases PD-L1 protein abundance and activates NF-κB signaling to trigger innate immune responses and MHC-I expression. Combining USP8 inhibitors with PD-1/PD-L1 blockers inhibited tumor growth and improved survival in CC mouse model ( 51 ). Conversely, high levels of USP8 may lead to T cell dysfunction, consistent with our results that USP8 is a risky factor and its expression is negatively correlated with CD8 + T cells ( 51 , 52 ).…”

“…Combining USP8 inhibitors with PD-1/PD-L1 blockers inhibited tumor growth and improved survival in CC mouse model ( 51 ). Conversely, high levels of USP8 may lead to T cell dysfunction, consistent with our results that USP8 is a risky factor and its expression is negatively correlated with CD8 + T cells ( 51 , 52 ). UBE2B , UBE2G2 , UBE2E2 and UBE2K are all E2 ubiquitin-conjugating enzymes and E2s are classified into four different types ( 53 ).…”

Current insight into the regulation of PD-L1 in cancer

“…CC[ 99 ], colon cancer[ 100 ], melanoma[ 101 , 102 , 106 ], lung cancer[ 101 ], esophageal squamous cell carcinoma[ 105 ]…”

“…LPS or high-cholesterol diet (HCD)-induced macrophage infiltration significantly activates the C-C motif chemokine ligand 5 (CCL5)-P65/STAT3-CSN5-PD-L1 signaling pathway in azoxymethane-induced CC mouse models and is correlated with poor prognosis [ 99 ]. In contrast to CSN5, the deubiquitinase USP8 removes TNF receptor associated factor 6 (TRAF6)-mediated K63-linked ubiquitination, thereby promoting PD-L1 degradation in mouse models of lung and colon cancer [ 100 ]. Ubiquilin 4 (UBQLN4) suppresses PD-L1 ubiquitination and promotes protein stability in melanoma.…”

“…MLL1 ↑PC [134] NRF2 ↑HCC [22] ATF3 ↑melanoma and NSCLC [55] Epigenetic regulation of PD-L1 DNA methylation ↓melanoma [62,64], leukemia [39] Histone modification ↓BC and B cell lymphomas [53,185], lung cancer [66] MicroRNAs shown in Table 1 N6-methyladenosine ↑OSCC [90], ↑BC [91] LncRNA and circRNA HOTTIP, SNHG12, EMX2OS-↑OC[76, 77, 81] SNHG20-↑esophagus cancer [78] CASC11-↑HCC [80] SNHG14-↑DLBCL [79] NUTM2A-AS1-↑GC [82] Hoxa-AS2-↑nasopharyngeal carcinoma [83] IFITM4P-↑OSCC [84] LncMX1-215-↓HNSCC [85] Hsa_circ_0000190-↑NSCLC [186] HasCircRNA-002178-↑ LUAD [87] CDR1-AS-↑CC [88] PD-L1 regulation at the protein level Ubiquitination ↓ BC [97], NSCLC [98], CC [99], colon cancer [100], melanoma [101,102,106], lung cancer [101], esophageal squamous cell carcinoma [105] Glycosylation ↑AML [108], TNBC [109,111], colon cancer [110], prostate cancer [111], glioma [112] Phosphorylation ↓ BC [114,116], HCC [115] Acetylation ↓ multiple cancers [117] Palmitoylation ↑ BC and colon cancer [118,…”