17P - Exploiting the immune-modulatory effects of PI3K/mTOR inhibitors to enhance response to immune-checkpoint blockade in uterine leiomyosarcoma

Background

Uterine leiomyosarcomas (uLMS) are aggressive tumors with poor prognosis and high risk of hematologic spread. Currently, no effective therapeutic agents are available for metastatic and relapsed cases. In general, uLMS are considered ‘immune-desert' tumors with very low levels of immune infiltration and therefore not prone to respond to immune checkpoint blockade (ICB). Recent research has focused on identifying feasible approaches to inflame ‘immune-desert’ tumors and prime them for ICB. Here we show that PI3K/mTOR inhibitors (PI3K/mTORi) are able to substantially remodel the TME of uLMS with high S6 phosphorylation levels (pS6^high), and promote responses to PD-1 blockade.

Methods

hCD34+ hematopoeitic stem cell engrafted (Transcure, France) and immunocompromised uLMS patient-derived xenografts (PDXs) were treated with combinations of (i) sapanisertib (0.3 mg/kg/day) + alpelisib (25 mg/kg/day), (ii) nivolumab (10 mg/kg, 2/wk) or (iv) vehicle. Tumor biopsies were collected pre- and post-treatment and subjected to bulk and single-cell RNA/TCR sequencing and multiplex immunohistochemistry. Data analysis was performed in R.

Results

Transcriptional profiling of pre- and post-treatment biopsies revealed that PI3K/mTORi induce a pro-inflammatory expression profile in pS6^high uLMS PDXs. In humanized pS6^high uLMS PDXs treatment with PI3K/mTORi leads to tumor growth suppression vs. resistance development and regrowth in immunodeficient PDXs, suggesting PI3K/mTORi are able to promote an anti-tumor immune response in an immunocompetent background. When combining PI3K/mTORi with anti-PD-1 blockade, a synergistic response was observed leading to partial or complete responses. Tumors treated with PI3K/mTORi and anti-PD-1 blockers show high levels of clonally expanded, tumor-infiltrating T-cells with enhanced expression of activation and cytotoxicity markers.

Conclusions

Here, we show that PI3K/mTOR inhibitors are able to enhance immune infiltration in humanized pS6^high uLMS PDXs and sensitize these tumors for ICB.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Kom op Tegen Kanker.

Disclosure

All authors have declared no conflicts of interest.