Abstract 1248: Predictors of innate resistance to pembrolizumab in patients with microsatellite instability-high endometrial cancer

Introduction: Despite FDA approval of pembrolizumab in microsatellite instability-high (MSI-H)/mismatch repair deficient solid tumors, approximately half of patients with MSI-H endometrial cancer are treatment-refractory. We sought to evaluate pre-treatment MSI-H endometrial tumor samples to examine cell subpopulation differences in the tumor microenvironment (TME) associated with resistance to pembrolizumab. Methods: Archival tumor samples from MSI-H endometrial cancer patients treated with pembrolizumab at MD Anderson Cancer Center were obtained under an IRB-approved protocol. Twenty-one patients were identified, and pre-treatment archival tumor samples were collected and submitted for RNA-seq and imaging mass cytometry (IMC) with an optimized 38-antibody panel to identify predictive immuno-genomic signatures and cell subpopulations associated with treatment response. Results: Among the 21 patients treated with pembrolizumab, there were 14 responders and 7 non-responders. Based on transcriptomic signatures, TME heterogeneity was observed. The 14 responders consisted of samples with immunologically “hot” (5/5; 100%), “cold” (6/8; 75%), and “warm” TMEs (3/8; 37.5%) while the 7 non-responders consisted of only “cold” (2/8; 25%) and “warm” (5/8; 62.5%) TME samples. There was an enrichment of fibroblasts and endothelial cell transcriptomic signatures in the samples of the non-responders compared to responders (p=0.018) with a trend of increasing enrichment in those signatures as response strength decreased. IMC performed on archival tissue from 20 patients demonstrated similar trend of higher population of activated fibroblasts (SMA+, MFAP5+) and endothelial cells (CD31+) in non-responders. Furthermore, non-responders had significantly higher total regulatory T cells (CD4+FOXP3+) in the tumor (p=0.027) and stroma (p=0.0282) compared to responders. Additionally, significantly higher activated regulatory T cells (CD4+FOXP3+CD25+) were observed in the tumor (p=0.016) and stroma (p=0.008) of non-responders compared to responders. Similar abundance of total and subpopulations of CD8+ T cells were observed between responders and non-responders. Conclusion: The MSI-H endometrial TME is heterogeneous. Increased presence of fibroblasts, endothelial cells, and regulatory T-cells in the TME correlate with innate resistance to pembrolizumab. Treatment aimed toward the reduction of these cellular subpopulations may improve sensitivity to PD-1 inhibitors. Future studies are needed to validate these findings. Citation Format: Jeffrey A. How, Minghao Dang, Sammy Ferri-Borgogno, Elizabeth Euscher, Melinda S. Yates, Weiyi Peng, Shrina D. Patel, Jared J. Burks, Ivo Vletic, Javier Gomez, Karen Lu, Samuel C. Mok, Linghua Wang, Amir A. Jazaeri. Predictors of innate resistance to pembrolizumab in patients with microsatellite instability-high endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1248.