Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00
Summary: Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNB...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-08-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225012258 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849397430240411648 |
|---|---|
| author | Andrea Joaquin Garcia Takashi Semba Mattia Rediti Daniel J. McGrail Xuemei Xie Xiaoping Wang Dileep R. Rampa David Venet Laurence Buisseret Samira Majjaj Roswitha Kammler Marco Colleoni Sherene Loi Giuseppe Viale Meredith M. Regan Françoise Rothé Christos Sotiriou Naoto T. Ueno |
| author_facet | Andrea Joaquin Garcia Takashi Semba Mattia Rediti Daniel J. McGrail Xuemei Xie Xiaoping Wang Dileep R. Rampa David Venet Laurence Buisseret Samira Majjaj Roswitha Kammler Marco Colleoni Sherene Loi Giuseppe Viale Meredith M. Regan Françoise Rothé Christos Sotiriou Naoto T. Ueno |
| author_sort | Andrea Joaquin Garcia |
| collection | DOAJ |
| description | Summary: Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8+/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies. |
| format | Article |
| id | doaj-art-e87a0afb4f9a4fc08a2ad1bb66d5c104 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-e87a0afb4f9a4fc08a2ad1bb66d5c1042025-08-20T03:38:59ZengElsevieriScience2589-00422025-08-0128811296410.1016/j.isci.2025.112964Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00Andrea Joaquin Garcia0Takashi Semba1Mattia Rediti2Daniel J. McGrail3Xuemei Xie4Xiaoping Wang5Dileep R. Rampa6David Venet7Laurence Buisseret8Samira Majjaj9Roswitha Kammler10Marco Colleoni11Sherene Loi12Giuseppe Viale13Meredith M. Regan14Françoise Rothé15Christos Sotiriou16Naoto T. Ueno17Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumSection of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, JapanBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, ItalyLerner Research Institute, Cleveland, OH, USACancer Biology Program, University of Hawaiʻi Cancer Center, Honolulu, HI, USACancer Biology Program, University of Hawaiʻi Cancer Center, Honolulu, HI, USACancer Biology Program, University of Hawaiʻi Cancer Center, Honolulu, HI, USABreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumTranslational Research Coordination International Breast Cancer Study Group, Division of ETOP IBCSG Partners Foundation, Bern, SwitzerlandInternational Breast Cancer Study Group, Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, ItalyInternational Breast Cancer Study Group, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, AustraliaIEO European Institute of Oncology IRCCS, Milan, ItalyInternational Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USABreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, BelgiumBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Corresponding authorCancer Biology Program, University of Hawaiʻi Cancer Center, Honolulu, HI, USASummary: Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8+/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.http://www.sciencedirect.com/science/article/pii/S2589004225012258ImmunologyCancerTranscriptomics |
| spellingShingle | Andrea Joaquin Garcia Takashi Semba Mattia Rediti Daniel J. McGrail Xuemei Xie Xiaoping Wang Dileep R. Rampa David Venet Laurence Buisseret Samira Majjaj Roswitha Kammler Marco Colleoni Sherene Loi Giuseppe Viale Meredith M. Regan Françoise Rothé Christos Sotiriou Naoto T. Ueno Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 iScience Immunology Cancer Transcriptomics |
| title | Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 |
| title_full | Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 |
| title_fullStr | Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 |
| title_full_unstemmed | Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 |
| title_short | Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00 |
| title_sort | role of immunosuppressive jnk pathway in the tumor microenvironment among tnbc subtypes in ibcsg trial 22 00 |
| topic | Immunology Cancer Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225012258 |
| work_keys_str_mv | AT andreajoaquingarcia roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT takashisemba roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT mattiarediti roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT danieljmcgrail roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT xuemeixie roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT xiaopingwang roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT dileeprrampa roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT davidvenet roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT laurencebuisseret roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT samiramajjaj roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT roswithakammler roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT marcocolleoni roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT shereneloi roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT giuseppeviale roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT meredithmregan roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT francoiserothe roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT christossotiriou roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 AT naototueno roleofimmunosuppressivejnkpathwayinthetumormicroenvironmentamongtnbcsubtypesinibcsgtrial2200 |