Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer
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ORIGINAL ARTICLE
Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer Alexandra Leary1,6 · Catherine Genestie2 · Félix Blanc‑Durand1 · Sébastien Gouy1 · Ariane Dunant3 · Amandine Maulard1 · Françoise Drusch2 · Bianca Cheaib5 · Judith Michels1 · Enrica Bentivegna1 · Audrey LeFormal4 · Soizick Mesnage4 · Philippe Morice1 · Patricia Pautier1 · Aya S. Khairallah2 Received: 6 February 2020 / Accepted: 9 July 2020 © The Author(s) 2020
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. Keywords Ovarian cancer · Microenvironment · TILs · Neoadjuvant chemotherapy · Immunotherapy
Background
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02670-0) contains supplementary material, which is available to authorized users. * Alexandra Leary [email protected] 1
Gynecological Cancer Unit, Department of Medicine, Institut Gustave Roussy, Villejuif, France
2
Pathology Department, Institut Gustave Roussy, Villejuif, France
3
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France
The majority of patients with epithelial ovarian cancer (EOC) present with advanced tumor stage (
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