Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer

Zhen Lu, Jinyun Chen, Pengfei Yu, Matthew J. Atherton, Jun Gui, Vivek S. Tomar, Justin D. Middleton, Neil T. Sullivan, Sunil Singhal, Subin S. George, Ashley G. Woolfork, Aalim M. Weljie, Tsonwin Hai, Evgeniy B. Eruslanov and Serge Y. Fuchs ()
Additional contact information
Zhen Lu: University of Pennsylvania
Jinyun Chen: University of Pennsylvania
Pengfei Yu: University of Pennsylvania
Matthew J. Atherton: University of Pennsylvania
Jun Gui: University of Pennsylvania
Vivek S. Tomar: University of Pennsylvania
Justin D. Middleton: The Ohio State University
Neil T. Sullivan: University of Pennsylvania
Sunil Singhal: University of Pennsylvania
Subin S. George: University of Pennsylvania
Ashley G. Woolfork: University of Pennsylvania
Aalim M. Weljie: University of Pennsylvania
Tsonwin Hai: The Ohio State University
Evgeniy B. Eruslanov: University of Pennsylvania
Serge Y. Fuchs: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.

Date: 2022
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DOI: 10.1038/s41467-022-34428-w

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