EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Abstract

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC).There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN-𝜸-induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain-binding protein 1-like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN-𝜸/JAK1/STAT1/PD-L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8 + T cell-mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD-L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient-derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

“…However, the efficacy of these therapies remains limited, with persistent immune suppression and resistance observed in the tumor microenvironment (TME). Therefore, it is imperative to identify new therapeutic targets to enhance the efficacy of immunotherapeutic agents for RCC 40 – 42 . Notably, targeting DHODH is a potential strategy for anti-ccRCC immunotherapy.…”

Reduced expression of cathepsin F predicts poor prognosis in patients with clear cell renal cell carcinoma

“…In addition, CTSF expression was negatively correlated with the expression of several immunoinhibitors (including CTLA4, TIGIT, CD96, LAG3, CD274, BTLA, PDCD1LG2 and PDCD1), immunostimulators (including ICOS, CD80, TNFRSF9, IL2RA, CD28, LTA, TNFSF13B, MICB, TNFSF4, TNFSF14, KLRK1 and CD86), and MHC molecules (including TAP1 and TAP2) in ccRCC. Published work have shown that high lymphocyte infiltration and immunosuppression characterized the immune microenvironment in ccRCC and contributed to cancer development 28 , 29 . Infiltration of CD8 + T cells within the tumor microenvironment (TME) may be associated with a poor prognostic marker and may predict the response to immune checkpoint blockade (ICB) in ccRCC 28 .…”

The role of IFN-γ-signalling in response to immune checkpoint blockade therapy

“…Furthermore, IFN-γ signalling can be effectively maintained within tumours through EH domain-binding protein 1-like protein 1 (EHBP1L1) shielding JAK1 from proteasomal degradation. This mechanism promoted PD-L1 expression in a mouse model of renal cell carcinoma (RCC) and EHBP1L1 inhibition resulted in increased CTL activity and improved response to ICBT [ 73 ].…”