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Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy
Olivia Le Saux1,2, Renaud Sabatier3,4, Isabelle Treilleux5,4
1Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, "Cancer Immune Surveillance and Therapeutic Targeting" Team, 28 rue Laennec, Lyon 69008, France.
Background:
Immune checkpoint inhibitors (ICIs) have shown efficacy in endometrial cancer (EC); however, their efficacy varies according to mismatch repair (MMR) status. Notably, even among patients with MMR-deficient (MMRd) or microsatellite instability-high (MSI-H) tumors, approximately one-third exhibit primary resistance to ICI monotherapy.
Objectives:
We aimed to characterize dissimilarities in the tumor immune microenvironment of ICI-treated MMRd/MSI-H versus MMR-proficient (MMRp)/microsatellite stable (MSS) EC, and to identify mechanisms of resistance.
Design:
Adults with histologically confirmed advanced or recurrent EC treated with ICIs in 6 French comprehensive cancer centers were included. Patients without available archival formalin-fixed paraffin-embedded primary tumor samples were excluded. Clinical data were collected retrospectively.
Methods:
Patients were classified as ICI-Responders or Non-Responders based on best objective response. A seven-color multi-immunofluorescence staining (CD20, CD4, CD8, FoxP3, CD68, CK, and DAPI) was performed on sections from archival formalin-fixed paraffin-embedded primary tumors. Cell densities and spatial proximity were analyzed using inForm software. T/B lymphoid aggregates (LA) and tertiary lymphoid structures (TLS) were separately quantified. Microsatellite status, presence of LA/TLS, and immune cell densities were correlated to response to treatment.
Results:
Twenty-one MMRd/MSI-H and 12 MMRp/MSS tumors were analyzed. We observed more MMRd/MSI-H tumors with LA/TLS compared to MMRp/MSS cases: 81% versus 17%, p ⩽ 0.001. There were more CD8+ T effector cells in the vicinity of B cells in MMRd/MSI-H tumors compared to MMRp/MSS tumors (1.26 (0-3.40) vs 0.49 (0-1.86), p = 0.017), suggesting cooperation between CD8+ T cells and B cells in MMRd/MSI-H tumors. No differences were shown in terms of the presence of LA/TLS and the subsequent response to ICI in EC (p = 0.400). Using a multivariate logistic regression model, we found that a low density of CD68+ tumor-associated macrophages (TAMs) in the stroma, was associated with response to ICI in EC (odds ratio = 11.67, 95% CI (1.69-237.45), p = 0.033) and showed good accuracy in predicting response to ICI in the whole cohort (AUC = 0.75, 95% CI (0.59-0.91)).
Conclusion:
We characterize the immune landscape in EC patients treated with ICIs. Distinct immune infiltrate patterns were observed in MMRd/MSI-H and MMRp/MSS tumors. A significant negative association between TAM density and ICI response was shown.
