In data from TCGA, upregulated expression of the long noncoding (lnc)RNA LINK-A was associated with immunosuppression and resistance to PD-1 blockade. In mouse mammary glands, transgenic LINK-A expression drove growth of TNBC-like tumors by inducing ubiquitination and degradation of tumor suppressors Rb and p53 and of components of the peptide-loading complex (PLC), reducing surface MHC-I expression. Treatment with LINK-A locked nucleic acids (LNA) or with the GPCR antagonist rauwolscine stabilized the PLC components, Rb, and p53, reducing tumor incidence and sensitizing resistant tumors to PD-1 blockade.
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
Author Info: (1) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Biochemistry and Molecular Biology, The Un
Author Info: (1) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. (3) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. College of Life Sciences, Zhejiang University, Hangzhou, China. (7) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. (11) Department of Biochemistry and Biology, University of Houston, Houston, TX, USA. UPMC Genome Center, Pittsburgh, PA, USA. (12) Department of Biochemistry and Biology, University of Houston, Houston, TX, USA. (13) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. (18) Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA. (19) Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA. (20) Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA. (21) Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA. Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA. (22) Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA. Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA. (23) Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA. (24) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, NC, USA. (26) Department of Biochemistry and Biology, University of Houston, Houston, TX, USA. Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA. (27) Department of Breast Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Breast Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (32) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) China Medical University, Taichung, Taiwan. (34) Department of Immunology, Division of Basic Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. leng.han@uth.tmc.edu. (36) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. clin2@mdanderson.org. The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. clin2@mdanderson.org. (37) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org. The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org.
