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Cancer Cell

Cancer Cell

IF: 48.79
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Inhibiting intracellular CD28 in cancer cells enhances antitumor immunity and overcomes anti-PD-1 resistance via targeting PD-L1

Published:12 December 2024 DOI: 10.1016/j.ccell.2024.11.008
Zhen Yang, Xinpeng Liu, Jun Zhu, Yangyang Chai, Boyi Cong, Bo Li, Wanfeng Gao, Ye Hu, Mingyue Wen, Yanfang Liu, Li Fu, Xuetao Cao

Abstract

Deciphering mechanisms for cancer immune escape may provide targets for improving immunotherapy efficacy. By in?vivo genome-wide CRISPR loss-of-function screening in a mouse model of triple negative breast cancer (TNBC), we uncovered a non-classical function of Cd28 in cancer cells to promote immune escape. Knocking out Cd28 in cancer cells increased infiltration of type I conventional DC (cDC1) and activated tumor-specific CD8+ T?cells, and pharmaceutical inducible knockdown of Cd28 inhibited pre-established tumor growth and overcame anti-PD-1 resistance in?vivo. Furthermore, high expression of cancer cell CD28 in human TNBC tissues correlated with elevated PD-L1 expression, less CD8+ T?cell infiltration, and poor prognosis. Mechanistically, intracellular CD28 directly bound to Cd274 mRNA and recruited spliceosomal factor SNRPB2 to stabilize Cd274 mRNA in nucleus, promoting PD-L1 expression and immune escape. Therefore, disrupting cancer cell CD28-mediated immune escape may provide a potential approach to improve breast cancer immunotherapy.

Substances (7)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Doxycycline hyclate 24390-14-5 C24H31ClN2O9 616 suppliers $17.47-$1650.00
PUROMYCIN DIHYDROCHLORIDE 58-58-2 C22H30ClN7O5 302 suppliers $11.00-$5076.00
Deoxyribonuclease 9003-98-9 NULL 290 suppliers $58.00-$2170.00
MK-2206 2HCl 1032350-13-2 C25H22ClN5O 213 suppliers $10.00-$5132.00
G418 49863-47-0 C20H40N4O10 75 suppliers Inquiry
HEXADIMETHRINE BROMIDE 28728-55-4 C39H90Br6N6X2 69 suppliers $65.10-$950.00
DAPI 47165-04-8 C16H15N5 13 suppliers $504.53-$504.53

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