Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression

Sara Zahraeifard, Zhiguang Xiao, Jae Young So, Abdul Ahad, Selina Montoya, Woo Yong Park, Trinadharao Sornapudi, Tiffany Andohkow, Abigail Read, Noemi Kedei, Vishal Koparde, Howard Yang, Maxwell Lee, Nathan Wong, Maggie Cam, Kun Wang, Eytan Ruppin, Ji Luo, Christine Hollander and Li Yang ()
Additional contact information
Sara Zahraeifard: National Cancer Institute, National Institutes of Health
Zhiguang Xiao: National Cancer Institute, National Institutes of Health
Jae Young So: National Cancer Institute, National Institutes of Health
Abdul Ahad: National Cancer Institute, National Institutes of Health
Selina Montoya: National Cancer Institute, National Institutes of Health
Woo Yong Park: National Cancer Institute, National Institutes of Health
Trinadharao Sornapudi: National Cancer Institute, National Institutes of Health
Tiffany Andohkow: National Cancer Institute, National Institutes of Health
Abigail Read: National Cancer Institute, National Institutes of Health
Noemi Kedei: National Cancer Institute, National Institutes of Health
Vishal Koparde: National Cancer Institute, National Institutes of Health
Howard Yang: National Cancer Institute, National Institutes of Health
Maxwell Lee: National Cancer Institute, National Institutes of Health
Nathan Wong: National Cancer Institute, National Institutes of Health
Maggie Cam: National Cancer Institute, National Institutes of Health
Kun Wang: National Cancer Institute, National Institutes of Health
Eytan Ruppin: National Cancer Institute, National Institutes of Health
Ji Luo: National Cancer Institute, National Institutes of Health
Christine Hollander: National Cancer Institute, National Institutes of Health
Li Yang: National Cancer Institute, National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50262-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50262-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50262-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().