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PP-24

Proteomic profiling identifies immune checkpoint suppression by

Ganoderma microsporum immunomodulatory protein (GMI) with enhanced

anti-tumor immunity

1,4
1
1
Wei-Jyun Hua, #,1,4 Li-Chen Huang, Zhi-Hu Lin, Yi-Ru Ciou, Tung-Yi Lin* ,1,2,3,4

1 Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221,
Taiwan.
2 School of Chinese Medicine, National Yang Ming Chiao Tung University, Taipei 11221,
Taiwan.
3 Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei
11221, Taiwan.
4 Traditional Chinese Medicine Glycomics Research Center, National Yang Ming Chiao Tung
University, Taipei 11221, Taiwan.
* E-mail: tylin99@nycu.edu.tw

Abstract
Cancer cells evade T cell responses by exploiting programmed death-ligand 1 (PD-L1) in the
tumor microenvironment, and oncogenic epidermal growth factor receptor (EGFR) signaling
stabilizes PD-L1 expression. Ganoderma microsporum immunomodulatory protein (GMI), a
consumable mushroom-derived dietary supplement, functions as an EGFR degrader targeting
EGFR-positive cancer cells. However, the role of GMI in regulating PD-L1 and modulating
anti-tumor immunity has not been fully elucidated. In this study, we first performed functional
enrichment on the differentially expressed proteins identified by our proteomic analysis to
characterize GMI-regulated pathways. The findings indicated that GMI may modulate the PD-
L1 signaling pathway. GMI downregulated PD-L1 expression by regulating both mRNA and
protein stability, thereby suppressing PD-L1-positive lung cancer cells in vitro and in vivo.
Functional studies further demonstrated that GMI promotes glycogen synthase kinase 3 beta
(GSK3β)-mediated proteasomal degradation of PD-L1. Knockdown of GSK3β in lung cancer
cells abolished the GMI-induced reduction in PD-L1 expression. Additionally, GMI inhibited
tumor growth and reduced PD-L1 levels in allograft mouse models. Importantly, GMI-mediated
PD-L1 downregulation correlated with enhanced T cell-mediated inhibition of lung cancer cells.
These findings shed light on the potential of edible GMI to boost anti-tumor immunity.

Keywords: Ganoderma microsporum immunomodulatory protein; Lung cancer; PD-L1
degradation; Proteasomal pathway; Anti-tumor immunity