26P - Predictive biomarker discovery for ICI treatment response in metastatic MMRd endometrial cancer through deep proteomic profiling of FFPE tissue samples

Background

MMRd status is a robust predictive biomarker for ICI in EC, however half of these pts do not respond. Most studies exploring biomarkers of response to ICI have focused on tumor or immune cell factors. We deployed a mass spectrometry-based unbiased quantitative proteomics profiling workflow to investigate the tumor microenvironment (TME) in ICI-Responder (R) versus Non-Responder (NR) MMRd EC patients to identify new predictive biomarkers of response.

Methods

Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI at Gustave Roussy Institute (2016-2021), were retrospectively collected. Patients were classified as Rs (CR, PR, or SD ≥12 months) or NRs (PD or SD <12 months). Pre-ICI FFPE tumor samples were subjected to Biognosys UltraDeep TrueDiscovery™ Mass Spectrometry (MS) for the identification of differentially regulated protein expression between R and NR.

Results

Unbiased quantitative mass spectrometry approach quantified in total 11187 proteins across 25 patient FFPE samples (17 responders and 8 non-responders). Given the limited statistical power due to the cohort size, the data were explored with both data-driven and hypothesis-driven methods. Eight biological hypotheses for treatment resistance in MMRd endometrial cancer were evaluated using the unbiased proteomics data while three key mediators of resistance are supported by measured protein expression profiles: 1) significantly increased abundance of collagens in non-responders indicate hindered immune cell infiltration: 2) local, acute inflammation based on the accumulation of CRP in the tumor microenvironment; 3) increased TGF-beta expression with associated immunosuppressive effect. To further validate these three observations, orthogonal experimental methods will be employed.

Conclusions

Unbiased proteomics data from FFPE tissue samples could confirm several TME-related hypotheses for ICI resistance in MMRd endometrial cancer patients. Further mechanistic studies are being performed to assess the actionability of these findings. In addition, an independent patient cohort will be involved as a follow-up validation study.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Institute Gustave Roussy.

Funding

Comprehensive Program of Cancer Immunotherapy & Immunology I (CAIMI-I) supported by the BBVA Foundation (grant 89/2017) - Program Parrainage pour la Recherche contre les Cancers Gynécologiques-IGR.

Disclosure

All authors have declared no conflicts of interest.