Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3.
T-lymphocytes
immunotherapy
lymphocytes
tumor-infiltrating
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
accepted:
13
09
2020
entrez:
23
10
2020
pubmed:
24
10
2020
medline:
6
10
2021
Statut:
ppublish
Résumé
Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8 These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.
Sections du résumé
BACKGROUND
Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors.
METHODS
Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later.
RESULTS
As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8
CONCLUSIONS
These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.
Identifiants
pubmed: 33093155
pii: jitc-2020-000693
doi: 10.1136/jitc-2020-000693
pmc: PMC7583804
pii:
doi:
Substances chimiques
Antigens, CD
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Pik3cd protein, mouse
EC 2.7.1.137
Lymphocyte Activation Gene 3 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209213/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 25722
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C16731/A21200
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C23338/A25722
Pays : United Kingdom
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: BV is a consultant for Karus Therapeutics (Oxford, UK), iOnctura (Geneva, Switzerland) and Venthera (Palo Alto, USA) and has received speaker fees from Gilead.
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