PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6
Tumor Microenvironment
/ drug effects
Leiomyosarcoma
/ drug therapy
Humans
Female
Uterine Neoplasms
/ drug therapy
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Phosphatidylinositol 3-Kinases
/ metabolism
Immune Checkpoint Inhibitors
/ pharmacology
MTOR Inhibitors
/ pharmacology
Animals
Mice
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
PI3K/mTOR inhibitors
anti‐PD‐1 therapy
humanized patient‐derived xenograft models
immune‐modulation
resistance
uterine leiomyosarcoma
Journal
Clinical and translational medicine
ISSN: 2001-1326
Titre abrégé: Clin Transl Med
Pays: United States
ID NLM: 101597971
Informations de publication
Date de publication:
May 2024
May 2024
Historique:
revised:
24
03
2024
received:
16
10
2023
accepted:
26
03
2024
medline:
7
5
2024
pubmed:
7
5
2024
entrez:
7
5
2024
Statut:
ppublish
Résumé
Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging-to-treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient-derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single-agent and a combination of PI3K/mTOR inhibitors with PD-1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single-cell RNA/TCR sequencing of serially collected biopsies. PI3K/mTOR over-activation (pS6 Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.
Sections du résumé
BACKGROUND
BACKGROUND
Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging-to-treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB.
METHODS
METHODS
We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient-derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single-agent and a combination of PI3K/mTOR inhibitors with PD-1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single-cell RNA/TCR sequencing of serially collected biopsies.
RESULTS
RESULTS
PI3K/mTOR over-activation (pS6
CONCLUSIONS
CONCLUSIONS
Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Immune Checkpoint Inhibitors
0
MTOR protein, human
EC 2.7.1.1
MTOR Inhibitors
0
Phosphoinositide-3 Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1655Subventions
Organisme : Kom op tegen Kanker
ID : #11040
Organisme : Stichting Tegen Kanker
ID : #2016-054
Organisme : Fonds Wetenschappelijk Onderzoek
ID : 1124423N
Organisme : HORIZON EUROPE Marie Sklodowska-Curie Actions
ID : #101064216
Informations de copyright
© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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