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



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.



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.



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.
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Medical Oncology, Barts Health NHS Trust, London, United Kingdom.
Steffen
S
Böhm
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Anne
A
Montfort
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Oliver M T
OM
Pearce
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Joanne
J
Topping
Bioinformatics Core, The Francis Crick Institute, London, United Kingdom.
Probir
P
Chakravarty
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Gemma L A
GL
Everitt
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Andrew
A
Clear
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
Jackie R
JR
McDermott
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.
Darren
D
Ennis
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Thomas
T
Dowe
Medical Oncology, Barts Health NHS Trust, London, United Kingdom.
Amanda
A
Fitzpatrick
Gynaecological Oncology, Barts Health NHS Trust, London, United Kingdom.
Elly C
EC
Brockbank
Gynaecological Oncology, Barts Health NHS Trust, London, United Kingdom.
Alexandra C
AC
Lawrence
Gynaecological Oncology, Barts Health NHS Trust, London, United Kingdom.
Arjun
A
Jeyarajah
Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
Asma Z
AZ
Faruqi
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.
Iain A
IA
McNeish
Department of Pathology, Barts Health NHS Trust, London, United Kingdom.
Naveena
N
Singh
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Medical Oncology, Barts Health NHS Trust, London, United Kingdom.
Michelle
M
Lockley
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. f.balkwill@qmul.ac.uk.
Frances R
FR
Balkwill
D000328:Adult; D060890:B7-H1 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor