Abstract 550P
Background
MMRd status is a predictive biomarker for ICI in EC, however half of MMRd EC pts do not respond. We aimed to describe the immune tumor microenvironment (iTME) in R versus NR MMRd EC pts to identify new predictive biomarkers for ICI beyond MMR or TMB status.
Methods
Clinical data and outcomes of metastatic MMRd EC pts, treated with ICI at Gustave Roussy (2016-2021), were retrospectively collected. Pts were classified as ICI-Responders (R) (CR, PR, or SD ≥12 months) or Non-Responders (NR) (PD or SD <12 months). Multiplexed Immunofluorescence and Immunohistochemistry panels were performed for CD4, CD3, CD8, CD57, CK, FOXP3, CD68, CD163, DC-Lamp (quantified by + cells, % + surface, semi-quantitative score), and HLA-I (>90%: Intact expression ; 90-10%/<10%: Subclonal/Diffuse Loss). Non-parametric statistical tests were used. By a semi-quantitative score, 3 immune profiles were established: High and Low T-cell (2+/3+ and 0/1+ CD3+ cell intraepithelial infiltration, respectively), and High B-cell (2+/3+ CD20+ cell infiltration in the tumor area and/or stroma).
Results
Twenty-two pts were identified: 11 R and 11 NR. Most had endometrioid histology (73%), MLH1/PMS2 loss (86%) with confirmed MLH1 promoter hypermethylation (68%), and had previously received platinum-based therapy (87%). Most MMRd EC had High T-cell (17/22) and among R, 91% (10/11) had High T-cell. Among those with Low T-cell, 80% (4/5) were NR. Only 3 pts had High B cell, and all of them were Rs. Rs showed significantly higher pre-ICI NK (CD3-/CD8+ cells) (p=0.01), a trend for higher CD8+ [Median (M): 160 vs 121 cells/mm2] and DC-Lamp+ cells (0.04 vs 0.02 cells/mm2), but lower Tregs (44 vs. 62 cells/mm2). Regarding HLA-I expression, 80% (4/5) of pt with diffuse HLA-I loss were NR. In an NR with pre-/post-ICI biopsies, progression on ICI was associated with decreases in CD4+, CD8+, NK, CD20+ (15-,5-,100-,100-fold, respectively) and a 1.5-fold increase in CD163+ cells.
Conclusions
Beyond High T-cell, our study suggests that High NK and B-cell infiltration may predict response to ICI in MMRd EC pts, while HLA-I diffuse loss may be associated with lack of clinical benefit. iTME changes under treatment may uncover escape mechanisms.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Comprehensive Program of Cancer Immunotherapy and Immunology I supported by BBVA Foundation (grant 89/2017).
Disclosure
M. Kfoury: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Role: GSK. P. Morice: Financial Interests, Personal, Advisory Board: AZ, GSK. P. Pautier: Financial Interests, Personal, Advisory Board, 2015, 2022: PharmaMar; Financial Interests, Institutional, Advisory Board, 2020: Roche, Clovis; Financial Interests, Institutional, Advisory Board, 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, 2019-2020: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, 2018-2019: Roche; Financial Interests, Institutional, Expert Testimony, 2022: MSD. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: Tesaro, AZ, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AZ; Financial Interests, Institutional, Funding, CI clinical trial: AZ; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. All other authors have declared no conflicts of interest.