Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
Identifieur interne : 002F61 ( Ncbi/Curation ); précédent : 002F60; suivant : 002F62Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells.
Auteurs : Deepak Mittal [Australie] ; Franco Caramia [Australie] ; Stefan Michiels [France] ; Heikki Joensuu [Finlande] ; Pirkko-Liisa Kellokumpu-Lehtinen [Finlande] ; Christos Sotiriou [Belgique] ; Sherene Loi [Australie] ; Mark J. Smyth [Australie]Source :
- Cancer research [ 1538-7445 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Femelle, Humains, Interleukines (génétique), Lignée cellulaire tumorale, Lymphocytes T CD8+ (immunologie), Récepteur ErbB-2 (génétique), Récepteur ErbB-2 (métabolisme), Souris, Souris de lignée BALB C, Survie sans rechute, Transduction du signal, Tumeurs du sein (anatomopathologie), Tumeurs du sein (génétique).
- MESH :
- anatomopathologie : Tumeurs du sein.
- génétique : Interleukines, Récepteur ErbB-2, Tumeurs du sein.
- immunologie : Lymphocytes T CD8+.
- métabolisme : Récepteur ErbB-2.
- Animaux, Femelle, Humains, Lignée cellulaire tumorale, Souris, Souris de lignée BALB C, Survie sans rechute, Transduction du signal.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Interleukins, Receptor, ErbB-2.
- genetics : Breast Neoplasms.
- immunology : CD8-Positive T-Lymphocytes.
- chemical , metabolism : Receptor, ErbB-2.
- pathology : Breast Neoplasms.
- Animals, Cell Line, Tumor, Disease-Free Survival, Female, Humans, Mice, Mice, Inbred BALB C, Signal Transduction.
Abstract
The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer
DOI: 10.1158/0008-5472.CAN-15-1567
PubMed: 26744522
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Breast Neoplasms (genetics)</term>
<term>Breast Neoplasms (pathology)</term>
<term>CD8-Positive T-Lymphocytes (immunology)</term>
<term>Cell Line, Tumor</term>
<term>Disease-Free Survival</term>
<term>Female</term>
<term>Humans</term>
<term>Interleukins (genetics)</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Receptor, ErbB-2 (genetics)</term>
<term>Receptor, ErbB-2 (metabolism)</term>
<term>Signal Transduction</term>
</keywords>
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<term>Femelle</term>
<term>Humains</term>
<term>Interleukines (génétique)</term>
<term>Lignée cellulaire tumorale</term>
<term>Lymphocytes T CD8+ (immunologie)</term>
<term>Récepteur ErbB-2 (génétique)</term>
<term>Récepteur ErbB-2 (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Survie sans rechute</term>
<term>Transduction du signal</term>
<term>Tumeurs du sein (anatomopathologie)</term>
<term>Tumeurs du sein (génétique)</term>
</keywords>
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<term>Receptor, ErbB-2</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs du sein</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Breast Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Interleukines</term>
<term>Récepteur ErbB-2</term>
<term>Tumeurs du sein</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Lymphocytes T CD8+</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, ErbB-2</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur ErbB-2</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Breast Neoplasms</term>
</keywords>
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<term>Cell Line, Tumor</term>
<term>Disease-Free Survival</term>
<term>Female</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Signal Transduction</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Femelle</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Survie sans rechute</term>
<term>Transduction du signal</term>
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<front><div type="abstract" xml:lang="en">The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer</div>
</front>
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