Changes in the tumor immune microenvironment during disease progression in patients with ovarian cancer

Marie Christine Wulff Westergaard, Katy Milne, Magnus Pedersen, Thomas Hasselager, Lars Rønn Olsen, Michael S. Anglesio, Troels Holz Borch, Mia Kennedy, Gillian Briggs, Stacey Ledoux, Caroline Kreuzinger, Isabel von der Decken, Marco Donia, Dan Cacsire Castillo-Tong, Brad H. Nelson, Inge Marie Svane*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer-and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.

Original languageEnglish
Article number3828
JournalCancers
Volume12
Issue number12
Number of pages19
ISSN2072-6694
DOIs
Publication statusPublished - 2020

Keywords

  • Adaptive immune resistance
  • Immune checkpoints
  • Multicolor immunohistochemistry (IHC)
  • NanoString
  • Ovarian cancer
  • TILs
  • Tumor microenvironment

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