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Open Access 01-02-2021 | Ovarian Cancer | Original Article

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer

Authors: Alexandra Leary, Catherine Genestie, Félix Blanc-Durand, Sébastien Gouy, Ariane Dunant, Amandine Maulard, Françoise Drusch, Bianca Cheaib, Judith Michels, Enrica Bentivegna, Audrey LeFormal, Soizick Mesnage, Philippe Morice, Patricia Pautier, Aya S. Khairallah

Published in: Cancer Immunology, Immunotherapy | Issue 2/2021

Abstract

Background

At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations.

Materials and methods

Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS.

Results

NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445).

Conclusion

NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

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Title: Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer
Authors: Alexandra Leary
Catherine Genestie
Félix Blanc-Durand
Sébastien Gouy
Ariane Dunant
Amandine Maulard
Françoise Drusch
Bianca Cheaib
Judith Michels
Enrica Bentivegna
Audrey LeFormal
Soizick Mesnage
Philippe Morice
Patricia Pautier
Aya S. Khairallah
Publication date: 01-02-2021
Publisher: Springer Berlin Heidelberg
Keywords: Ovarian Cancer
Ovarian Cancer
Cytostatic Therapy
Published in: Cancer Immunology, Immunotherapy / Issue 2/2021
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02670-0

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