The UBA1-STUB1 axis mediates cancer immune escape and resistance to checkpoint blockade.

Autor:	Bao Y; University of Michigan, Ann Arbor, United States., Cruz G; University of Michigan-Ann Arbor, United States., Zhang Y; University of Michigan-Ann Arbor, United States., Qiao Y; University of Michigan-Ann Arbor, Singapore, Singapore., Mannan R; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Hu J; University of Michigan-Ann Arbor, United States., Yang F; University of Michigan-Ann Arbor, United States., Gondal M; University of Michigan-Ann Arbor, United States., Shahine M; University of Michigan-Ann Arbor, United States., Kang S; University of Michigan-Ann Arbor, United States., Mahapatra S; University of Michigan-Ann Arbor, Ann ARbor, United States., Chu A; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Choi JE; University of California San Francisco, Ann Arbor, United States., Yu J; University of Michigan-Ann Arbor, Ann Arbor, United States., Lin H; University of Michigan School of Medicine, Ann Arbor, MI, United States., Miner SJ; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Robinson DR; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Wu YM; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Zheng Y; University of Michigan-Ann Arbor, Ann Arbor, United States., Cao X; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Su F; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Wang R; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Hosseini N; University of Michigan-Ann Arbor, United States., Cieslik M; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Kryczek I; University of Michigan School of Medicine, Ann Arbor, MI, United States., Vaishampayan U; University of Michigan-Ann Arbor, Ann Arbor, Michigan, United States., Zou W; University of Michigan-Ann Arbor, Ann Arbor, MI, United States., Chinnaiyan AM; University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Nov 14. Date of Electronic Publication: 2024 Nov 14.
DOI:	10.1158/2159-8290.CD-24-0435
Abstrakt:	How cancer cells escape immune surveillance and resist immune checkpoint blockade (ICB) remains to be fully elucidated. By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like modifier activating enzyme 1 (UBA1) as being the most negatively correlated with signatures related to effector CD8+ T-cells. High UBA1 expression was strongly predictive of treatment resistance and poor survival in ICB cohorts. Functional studies revealed that UBA1 mediated immune escape to promote tumor growth. Immune profiling further showed that Uba1 overexpression or depletion markedly decreased or increased functional intratumoral CD8+ T-cells, respectively. Importantly, a selective UBA1 inhibitor, TAK-243, significantly synergized with ICB in multiple syngeneic models. Mechanistically, depletion or inactivation of the UBA1-STUB1 axis stabilized a key interferon pathway component (JAK1), enhanced IFN-signaling, and elevated key immune modulators, including CXCL9, CXCL10, and MHC class I. Our study warrants clinical evaluation of the combination of UBA1 inhibitors and ICB.
Databáze:	MEDLINE
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