PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6 high uterine leiomyosarcoma to PD-1 blockade.

Autor: De Wispelaere W; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium.; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Annibali D; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium.; Department of Gynecological Oncology, Antoni Van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands., Tuyaerts S; Department of Medical Oncology, Laboratory of Medical and Molecular Oncology (LMMO), Vrije Universiteit Brussel - UZ Brussel, Brussels, Belgium., Messiaen J; Department of Imaging and Pathology, Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium.; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium., Antoranz A; Department of Imaging and Pathology, Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium., Shankar G; Department of Imaging and Pathology, Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium., Dubroja N; Department of Imaging and Pathology, Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium., Herreros-Pomares A; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium.; Department of Biotechnology, Universitat Politècnica de Valencia, Valencia, Spain., Baiden-Amissah REM; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium., Orban MP; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium.; Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), University of Leuven, Leuven, Belgium., Delfini M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium.; Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), University of Leuven, Leuven, Belgium., Berardi E; Department of Development and Regeneration, Laboratory of Tissue Engineering, University of Leuven, Kortrijk, Belgium., Van Brussel T; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Schepers R; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Philips G; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Boeckx B; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Baietti MF; TRACE, Department of Oncology, University of Leuven, Leuven, Belgium., Congedo L; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium., HoWangYin KY; TransCure bioServices, Archamps, France., Bayon E; TransCure bioServices, Archamps, France., Van Rompuy AS; Department of Pathology, University Hospitals Leuven, Leuven, Belgium., Leucci E; TRACE, Department of Oncology, University of Leuven, Leuven, Belgium., Tabruyn SP; TransCure bioServices, Archamps, France., Bosisio F; Department of Imaging and Pathology, Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium., Mazzone M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium.; Department of Oncology, Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), University of Leuven, Leuven, Belgium., Lambrechts D; Department of Human Genetics, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.; Laboratory for Translational Genetics, Center for Cancer Biology (CCB), Flemish Institute of Biotechnology (VIB), Leuven, Belgium., Amant F; Department of Oncology, Laboratory of Gynecological Oncology, University of Leuven, Leuven, Belgium.; Department of Gynecological Oncology, Antoni Van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2024 May; Vol. 14 (5), pp. e1655.
DOI: 10.1002/ctm2.1655
Abstrakt: 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: 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: PI3K/mTOR over-activation (pS6 high ) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB-resistant humanized uLMS PDX model, fostering adaptive anti-tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti-tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD-1+ T cells displaying an exhausted phenotype. When combined with anti-PD-1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single-agent anti-PD-1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper-expansion of a cytotoxic CD8+ T-cell population supported by a CD4+ T h 1 niche.
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.
(© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje