Intratumoral TREX1 induction promotes immune evasion by limiting type I IFN Journal Article
| Authors: | Toufektchan, E.; Dananberg, A.; Striepen, J.; Hickling, J. H.; Shim, A.; Chen, Y.; Nichols, A.; Paez, M. A. D.; Mohr, L.; Bakhoum, S. F.; Maciejowski, J. |
| Article Title: | Intratumoral TREX1 induction promotes immune evasion by limiting type I IFN |
| Abstract: | Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation of the nuclease TREX1 as an adaptive, negative feedback mechanism that promotes immune evasion through digestion of cytosolic DNA. TREX1 loss diminishes tumor growth, prolongs survival of host animals, increases tumor immune infiltration, and potentiates response to immune checkpoint blockade selectively in tumors capable of mounting a type I IFN response downstream of STING. Together, these data demonstrate that TREX1 induction shields chromosomally unstable tumors from immune surveillance by dampening type I IFN production and suggest that TREX1 inhibitors might be used to selectively target tumors that have retained the inherent ability to mount an IFN response downstream of STING. © 2024 The Authors. |
| Keywords: | controlled study; unclassified drug; human cell; overall survival; genetics; interferon; nonhuman; neoplasm; neoplasms; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; animal tissue; gene expression profiling; cell line; animal experiment; animal model; membrane proteins; cell line, tumor; wild type; enzyme linked immunosorbent assay; mice, inbred c57bl; c57bl mouse; colorectal carcinoma; immunology; immune response; immunotherapy; messenger rna; membrane protein; tumor cell line; immunoblotting; protein induction; phosphoproteins; chromosomal instability; real time polymerase chain reaction; upregulation; negative feedback; tumor growth; immunosurveillance; cell suspension; phosphoprotein; knockout mouse; immunofluorescence microscopy; regulator protein; exodeoxyribonuclease; exodeoxyribonucleases; nucleotidyltransferase; immune evasion; nucleotidyltransferases; interferon type i; life extension; tumor escape; immunoglobulin g2a antibody; humans; human; female; article; clustered regularly interspaced short palindromic repeat; antigenic escape; interferon signaling; trex1 protein; sting1 protein, human; three prime repair exonuclease 1; ct26 cell line; type i interferon signaling |
| Journal Title: | Cancer Immunology Research |
| Volume: | 12 |
| Issue: | 6 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-06-01 |
| Start Page: | 673 |
| End Page: | 686 |
| Language: | English |
| DOI: | 10.1158/2326-6066.Cir-23-1093 |
| PUBMED: | 38408184 |
| PROVIDER: | scopus |
| PMCID: | PMC11148545 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding authors is MSK author: John Maciejowski -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work