Ubiquitin-Conjugating Enzyme Ubc13 in Macrophages Suppresses Lung Tumor Progression Through Inhibiting PD-L1 Expression

Abstract

Tumor cell-intrinsic ubiquitin-conjugating enzyme Ubc13 promotes tumorigenesis, yet how Ubc13 in immune cell compartments regulates tumor progression remains elusive. Here, we show that myeloid-specific deletion of Ubc13 (Ubc13^fl/flLyz2^Cre) leads to accelerated transplanted lung tumor growth in mice. Compared with their littermate controls, tumor-bearing Ubc13^fl/flLyz2^Cre mice had lower proliferation and effector function of CD8⁺ T lymphocytes, accompanied by increased infiltration of myeloid-derived suppressor cells within the tumor microenvironment. Mechanistically, Ubc13 deficiency leads to upregulation of Arg1 and PD-L1, the latter is modulated by reduced Ubc13-mediated K63-linked polyubiquitination and increasing activation of Akt, thereby inducing skewness to protumoral polarization and immunosuppressive manifestation. Taken together, we reveal that macrophage-intrinsic Ubc13 restrains lung tumor progression, indicating that activating Ubc13 in macrophages could be an effective immunotherapeutic regimen for lung cancer.

Keywords: Lung cancer; PD‐L1; Ubc13; immunotherapy; macrophage.