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Clin Cancer Res. 2016 Jun 15;22(12):3025-36. doi: 10.1158/1078-0432.CCR-15-2657.

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma.

Author information

1
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Medical Oncology, Barts Health NHS Trust, London, United Kingdom.
2
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
3
Bioinformatics Core, The Francis Crick Institute, London, United Kingdom.
4
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
5
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
6
Medical Oncology, Barts Health NHS Trust, London, United Kingdom.
7
Gynaecological Oncology, Barts Health NHS Trust, London, United Kingdom.
8
Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
9
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. f.balkwill@qmul.ac.uk.

Abstract

PURPOSE:

The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.

EXPERIMENTAL DESIGN:

We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.

RESULTS:

There was evidence of T-cell activation in omental biopsies after NACT: CD4(+) T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8(+) T-cell and CD45RO(+) memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3(+) T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT.

CONCLUSIONS:

NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. ©2016 AACR.

PMID:
27306793
DOI:
10.1158/1078-0432.CCR-15-2657
[Indexed for MEDLINE]
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