소재영 (National Institutes of Health)

한빛사논문

조회263

National Institutes of Health

CV File 294 kb

Nat. Commun., Jul 12 2024, 15 (1) 5873 | https://doi.org/10.1038/s41467-024-50262-8 Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression

Sara Zahraeifard^1,6, Zhiguang Xiao^1,6, Jae Young So^1,6, Abdul Ahad¹, Selina Montoya¹, Woo Yong Park¹, Trinadharao Sornapudi¹, Tiffany Andohkow¹, Abigail Read¹, Noemi Kedei², Vishal Koparde^3,4, Howard Yang¹, Maxwell Lee¹, NathanWong^3,4, Maggie Cam³, KunWang⁵, Eytan Ruppin⁵, Ji Luo¹, Christine Hollander¹ & Li Yang¹

¹Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

²Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,MD 20892, USA.

³Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

⁴Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA.

⁵Cancer Data Science Laboratory, Center forCancer Research,NationalCancer Institute,National Institutes of Health, Bethesda,MD20892, USA.

⁶These authors contributed equally: Sara Zahraeifard, Zhiguang Xiao, Jae Young So.

Corresponding author

Correspondence to Li Yang.

Abstract

Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-β RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-β RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-β RII-inactivated cancers.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-26)
연구진국외 연구진
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