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. 2025 Aug 8:17:17588359251347364.
doi: 10.1177/17588359251347364. eCollection 2025.

Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy

Olivia Le Saux  1   2 , Renaud Sabatier  3   4 , Isabelle Treilleux  5   4 , Léa-Isabelle Renaud  6 , Pierre-Emmanuel Brachet  7 , Alejandra Martinez  8   4 , Jean-Sébastien Frenel  9   10 , Cyril Abdeddaim  11 , Justine Berthet  12   13 , Sarah Barrin  13 , Amélie Colombe-Vermorel  5 , Laetitia Odeyer  5 , Alexandra Lainé  14 , Christophe Caux  12   13 , Bertrand Dubois  12   13 , Isabelle Ray-Coquard  10   6
Affiliations

Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy

Olivia Le Saux et al. Ther Adv Med Oncol. .

Abstract

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.

Keywords: endometrial cancer; immune checkpoint inhibitors; macrophages.

Plain language summary

Exploring immune cells and tumor macrophages in endometrial cancer: insights for immunotherapy success Immune checkpoint inhibitors (ICIs) are promising treatments for endometrial cancer (EC), particularly in patients with specific genetic profiles, such as mismatch repair-deficient or microsatellite instability-high (MMRd/MSI-H) tumors. However, these treatments do not work for everyone, and many patients with MMRd/MSI-H tumors show resistance to ICIs. This study analyzed differences in the immune environment of EC tumors with and without these genetic markers to understand why some patients respond better to ICIs. Tumor samples from 33 patients treated with ICIs were studied using advanced staining techniques to visualize immune cells. Researchers also measured the densities of various immune cells, including T cells, B cells, and tumor-associated macrophages (TAMs), and examined their interactions within the tumors. The study found that MMRd/MSI-H tumors had more immune structures, such as lymphoid aggregates and tertiary lymphoid structures, compared to other types of EC. These tumors also showed more collaboration between two types of immune cells: CD8+ T cells (which attack cancer cells) and B cells. However, the presence of these structures did not predict whether patients would respond to ICI treatment. Interestingly, the researchers discovered that a lower number of TAMs, which can suppress the immune response, was strongly linked to better responses to ICIs. This finding suggests that TAM density could serve as a potential biomarker to predict which patients might benefit most from this therapy. Overall, this study highlights differences in immune environments between EC tumor types and identifies TAMs as a potential target to improve ICI efficacy. This research may help refine treatment strategies and improve outcomes for patients with endometrial cancer.

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Conflict of interest statement

A.M. received honoraria from GSK. J.-S.F. received honoraria from AstraZeneca, Daïchi, Pfizer, Lilly, Novartis, Gsk, MSD, Esai, and Seagen. I.R.-C. received research grants from MSD, Roche, BMS, GSK, Novartis, AstraZeneca, and Merck Sereno; honoraria from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; Springworks, Adaptimmune, Immunogen, Seagen, Novocure, Daichi Sankyo; and travel support from Roche, AstraZeneca, and GSK. R.S. received research grants from AstraZeneca, honoraria from AstraZeneca, GSK, Seagen, EISAI, Novartis, Clovis Oncology, and nonfinancial support from MSD, GSK, and Novartis. O.L.S. received research grants from AstraZeneca and honoraria from GSK, MSD, and Clovis Oncology.

Figures

Figure 1.
Figure 1.
Swimmer plot of treatment and disease course. Each bar represents a patient. *One hundred forty-two and one hundred eleven were treated with anti-PD1 + Netrin-1 inhibitor (NCT04652076) and 326 with anti-PD1 + IDO inhibitor (NCT03459222). MMRd, mismatch repair-deficient; MMRp, mismatch repair-proficient; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NR, nonresponder; R, responder.
Figure 2.
Figure 2.
Density of immune cells in endometrial cancer in the tumor and the stroma. (a) Multi-IF staining displaying a tumor sample with a sparse distribution of immune cells. (b) Illustration of the segmentation of the tumor slide into tumor islets (red), stroma (green), empty regions (yellow), and non-specific staining areas (blue). (c) Tumor sample with lymphoid aggregate. (d) Tumor sample featuring a TLS and intra-epithelial CD8+ T cells (in green). (e) Number of cells/mm2 (i.e., the density) of B cells, TAMs, CD4+ Th cells, CD4+ Tregs, CD8+ T cells (Teff), and CD8+/FOXP3+ T cells both in the stroma (left) and within tumor islets (right). Mean and standard deviations are displayed. Multi-IF, multiplexed-immunofluorescence; TAMs, tumor-associated macrophages; Th, T helper; TLS, tertiary lymphoid structure; Tregs, regulatory T cells.
Figure 3.
Figure 3.
A greater percentage of MMRd/MSI-H tumors exhibit LA/TLS in comparison to MMRp/MSS tumors. (a) Number of cells/mm2 (i.e., the density) of B cells, TAMs, CD4+ Th cells, CD4+ Tregs, CD8+ T cells (Teff), and CD8+/FOXP3+ T cells both in the stroma (left) and within tumor islets (right) in MMRd/MSI-H (magenta) and MMRp/MSS (dark green) tumors. (b) Proportion of MMRd/MSI-H (magenta)/MMRp/MSS (dark green) samples with (⩾1 LA in the sample or ⩾1 TLS in the sample) and without TLS (no TLS in the sample). Mean and standard deviations are displayed. p-Values <0.05 were considered significant, with stars corresponding to *p < 0.05; **p < 0.01; ***p < 0.001. If no stars are indicated, there was no statistically significant difference. LA, lymphoid aggregates; MMRd, mismatch repair-deficient; MMRp, mismatch repair-proficient; MSI-H, microsatellite instability-high; MSS, microsatellite stable; TAMs, tumor-associated macrophages; Th, T helper; TLS, tertiary lymphoid structure; Tregs, regulatory T cells.
Figure 4.
Figure 4.
Resistance to immune checkpoint inhibitors is associated with a significant abundance of TAMs in the stroma in EC. (a) Number of cells/mm2 (i.e., the density) of B cells, TAMs, CD4+ Th cells, CD4+ Tregs, CD8+ T cells (Teff), and CD8+/FOXP3+ T cells both in the stroma (left) and within tumor islets (right) in responders (R) (yellow) and NR (blue). Mean and standard deviations are displayed. (b) Proportion of R (yellow) and NR (blue) samples with (⩾1 LA in the sample or ⩾1 TLS in the sample) and without TLS (no TLS in the sample). p-Values <0.05 were considered significant, with stars corresponding to *p < 0.05. If no stars are indicated, no statistically significant difference was found. (c) ROC curves representing the area under the curve for the model considering a high/low proportion of TAMs in the stroma in the whole (blue), the MMRd/MSI-H (magenta), and MMRp/MSS (dark green) cohorts. (d) Survival curves representing the PFS (left) and OS (right) probability of patients presenting a low proportion of TAMs in the stroma (yellow) compared to others (blue). p-Values are calculated using a likelihood ratio test. p-Values <0.05 were considered significant, with stars corresponding to *p < 0.05, **p < 0.01. If no stars are indicated, there was no statistically significant difference. (e) Multiplex IF staining showing one NR EC patient with a high number of TAMs in the stroma and an R patient with few TAMs in the stroma. EC, endometrial cancer; LA, lymphoid aggregates; MMRd, mismatch repair-deficient; MMRp, mismatch repair-proficient; MMS, microsatellite stable; MSI-H, microsatellite instability-high; multi-IF, multiplexed-immunofluorescence; NR, nonresponders; OS, overall survival; PFS, progression-free survival; R, responders; TAMs, tumor-associated macrophages; Th, T helper; TLS, tertiary lymphoid structure; Tregs, regulatory T cells.
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