PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD-1 blockade

Wout De Wispelaere , Daniela Annibali , Sandra Tuyaerts , Julie Messiaen , Asier Antoranz , Gautam Shankar , Nikolina Dubroja , Alejandro Herreros-Pomares , Regina E. M. Baiden-Amissah , Marie-Pauline Orban , Marcello Delfini , Emanuele Berardi , Thomas Van Brussel , Rogier Schepers , Gino Philips , Bram Boeckx , Maria Francesca Baietti , Luigi Congedo , Kiave Yune HoWangYin , Emilie Bayon , Anne-Sophie Van Rompuy , Eleonora Leucci , Sebastien P. Tabruyn , Francesca Bosisio , Massimiliano Mazzone , Diether Lambrechts , Frédéric Amant

Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (5) : e1655

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Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (5) : e1655 DOI: 10.1002/ctm2.1655
RESEARCH ARTICLE

PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD-1 blockade

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Abstract

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 (pS6high) 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+ Th1 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.

Keywords

anti-PD-1 therapy / humanized patient-derived xenograft models / immune-modulation / PI3K/mTOR inhibitors / resistance / uterine leiomyosarcoma

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Wout De Wispelaere, Daniela Annibali, Sandra Tuyaerts, Julie Messiaen, Asier Antoranz, Gautam Shankar, Nikolina Dubroja, Alejandro Herreros-Pomares, Regina E. M. Baiden-Amissah, Marie-Pauline Orban, Marcello Delfini, Emanuele Berardi, Thomas Van Brussel, Rogier Schepers, Gino Philips, Bram Boeckx, Maria Francesca Baietti, Luigi Congedo, Kiave Yune HoWangYin, Emilie Bayon, Anne-Sophie Van Rompuy, Eleonora Leucci, Sebastien P. Tabruyn, Francesca Bosisio, Massimiliano Mazzone, Diether Lambrechts, Frédéric Amant. PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD-1 blockade. Clinical and Translational Medicine, 2024, 14(5): e1655 DOI:10.1002/ctm2.1655

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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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