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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. [ABSTRACT FROM AUTHOR]

Background: The phase II PRIMMO trial investigated a pembrolizumab-based regimen in patients with recurrent and/or metastatic cervical (CC) or endometrial (EC) carcinoma who had at least one prior line of systemic therapy. Here, exploratory studies of the gut microbiome (GM) are presented., Methods: The microbial composition of 77 longitudinal fecal samples obtained from 35 patients (CC, n = 15; EC, n = 20) was characterized using 16S rRNA gene sequencing. Analyses included assessment of alpha (Shannon index) and beta diversity (weighted UniFrac), unbiased hierarchical clustering, and linear discriminant analysis effect size. Correlative studies with demographics, disease characteristics, safety, efficacy, and immune monitoring data were performed., Results: Significant enrichment in multiple bacterial taxa was associated with the occurrence or resistance to severe treatment-related adverse events (overall or gastrointestinal toxicity specifically). Consistent differences in GM taxonomic composition before pembrolizumab initiation were observed between patients with favorable efficacy (e.g., enriched with Blautia genus) and those with poor efficacy (e.g., enriched with Enterobacteriaceae family and its higher-level taxa up to the phylum level, as well as Clostridium genus and its Clostridiaceae family). Two naturally occurring GM clusters with distinct bacterial compositions were identified. These clusters showed a more than four-fold differential risk for death (hazard ratio, 4.4 [95 % confidence interval, 1.9 to 10.3], P < 0.001) and were associated with interesting (but non-significant) trends in peripheral immune monitoring data., Conclusion: Although exploratory, this study offers initial insights into the intricate interplay between the GM and clinical outcomes in patients with CC and EC treated with a pembrolizumab-based regimen., Trial Registration: ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97)., Competing Interests: Declaration of competing interest EAD: travel and accommodation expenses (institutional, not personal) from AstraZeneca, GSK, and Pfizer. AMTV: became an employee for GSK during the publication development. PV: consulting or advisory role (personal) from Eli Lily and Company, MSD, Mundipharma, Novartis, Pfizer, and Roche; research funding from Tesaro. SH: consulting or advisory role (personal) from AstraZeneca, BMSi, Gilead Sciences, Merck, MSD Oncology, Novartis, and Sanofi. SA: consulting or advisory role (institutional, not personal) for MSD, Sanofi, Roche, BMS, and Pfizer; research funding (institutional, not personal) from Sanofi. AD: research funding (institutional, not personal) from AstraZeneca. EN: travel and accommodation expenses (institutional, not personal) from AstraZeneca, Novartis, Pfizer, PharmaMar, Roche, and Teva. FA: consulting or advisory role (institutional, not personal) for MiMark. KV: travel and accommodation expenses (institutional, not personal) from PharmaMar. HGD: travel and accommodation expenses (institutional, not personal) from Amgen, AstraZeneca, Eli Lily and Company, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, Tesaro, and Teva; research funding (institutional, not personal) from Roche. HH, ST, LL, RB, XBT, PAV, AH, OD, KKV, and BV: declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)