Simultaneous Inhibition of PI3Kgamma and PI3Kdelta Deteriorates T-cell Function With Implications for Chronic Lymphocytic Leukemia
Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association..
Chronic lymphocytic leukemia (CLL) is a common and incurable B-cell malignancy. Recent therapeutic approaches that target the B-cell receptor signaling pathway include inhibition of phosphatidylinositol-3-kinase (PI3K). The PI3K isoform delta is constitutively active in CLL, making it an attractive therapeutic target. However, the expression of PI3K isoforms is not exclusive to leukemic cells, as other immune cells in the tumor microenvironment also rely on PI3K activity. Subsequently, therapeutic inhibition of PI3K causes immune-related adverse events (irAEs). Here, we analyzed the impact of the clinically approved PI3Kδ inhibitors idelalisib and umbralisib, the PI3Kγ inhibitor eganelisib, and the dual-γ and -δ inhibitor duvelisib on the functional capacity of T cells. All investigated inhibitors reduced T-cell activation and proliferation in vitro, which is in line with PI3K being a crucial signaling component of the T-cell receptor signaling. Further, dual inhibition of PI3Kγ and PI3Kδ showed strong additive effects suggesting a role also for PI3Kγ in T cells. Extrapolation of this data to a clinical setting could provide an explanation for the observed irAEs in CLL patients undergoing treatment with PI3K inhibitors. Consequently, this highlights the need for a close monitoring of patients treated with PI3K inhibitors, and particularly duvelisib, due to their potentially increased risk of T-cell deficiencies and associated infections.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
HemaSphere - 7(2023), 3 vom: 14. März, Seite e840 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Faehling, Sebastian [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 28.02.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1097/HS9.0000000000000840 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM353503010 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM353503010 | ||
| 003 | DE-627 | ||
| 005 | 20231226060141.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1097/HS9.0000000000000840 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1178.xml |
| 035 | |a (DE-627)NLM353503010 | ||
| 035 | |a (NLM)36844182 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Faehling, Sebastian |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Simultaneous Inhibition of PI3Kgamma and PI3Kdelta Deteriorates T-cell Function With Implications for Chronic Lymphocytic Leukemia |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 28.02.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. | ||
| 520 | |a Chronic lymphocytic leukemia (CLL) is a common and incurable B-cell malignancy. Recent therapeutic approaches that target the B-cell receptor signaling pathway include inhibition of phosphatidylinositol-3-kinase (PI3K). The PI3K isoform delta is constitutively active in CLL, making it an attractive therapeutic target. However, the expression of PI3K isoforms is not exclusive to leukemic cells, as other immune cells in the tumor microenvironment also rely on PI3K activity. Subsequently, therapeutic inhibition of PI3K causes immune-related adverse events (irAEs). Here, we analyzed the impact of the clinically approved PI3Kδ inhibitors idelalisib and umbralisib, the PI3Kγ inhibitor eganelisib, and the dual-γ and -δ inhibitor duvelisib on the functional capacity of T cells. All investigated inhibitors reduced T-cell activation and proliferation in vitro, which is in line with PI3K being a crucial signaling component of the T-cell receptor signaling. Further, dual inhibition of PI3Kγ and PI3Kδ showed strong additive effects suggesting a role also for PI3Kγ in T cells. Extrapolation of this data to a clinical setting could provide an explanation for the observed irAEs in CLL patients undergoing treatment with PI3K inhibitors. Consequently, this highlights the need for a close monitoring of patients treated with PI3K inhibitors, and particularly duvelisib, due to their potentially increased risk of T-cell deficiencies and associated infections | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Coelho, Mariana |e verfasserin |4 aut | |
| 700 | 1 | |a Floerchinger, Alessia |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Christof |e verfasserin |4 aut | |
| 700 | 1 | |a Stilgenbauer, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Lichter, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Seiffert, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Roessner, Philipp M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t HemaSphere |d 2017 |g 7(2023), 3 vom: 14. März, Seite e840 |w (DE-627)NLM29509902X |x 2572-9241 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2023 |g number:3 |g day:14 |g month:03 |g pages:e840 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1097/HS9.0000000000000840 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2023 |e 3 |b 14 |c 03 |h e840 | ||