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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen / metabolism
  • Cytokines / blood
  • Cytoreduction Surgical Procedures
  • Female
  • Humans
  • Immunotherapy / methods
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Ovarian Neoplasms / pathology*
  • Ovarian Neoplasms / therapy
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytokines
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor