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Cancer Immunol Res. 2019 Mar 22. pii: canimm.0499.2018. doi: 10.1158/2326-6066.CIR-18-0499. [Epub ahead of print]

Multiple immune suppressive mechanisms in fibrolamellar carcinoma.

Author information

1
Medicine, Johns Hopkins University School of Medicine akim97@jhmi.edu.
2
SURGERY, Johns Hopkins University.
3
Department of Pathology, Johns Hopkins University School of Medicine.
4
Pathology, Johns Hopkins Medicine.
5
Dermatology, Johns Hopkins University.
6
Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine.
7
AmeriPath Indiana.
8
School of Medicine, University College Dublin.
9
Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center.
10
Department of Surgery, Ohio State University Wexner Medical Center.
11
Department of Oncology - Gastrointestinal Cancer, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
12
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.
13
Research, Canadian Foundation for Translational Immunology.
14
Johns Hopkins University.

Abstract

Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8+ cytotoxic T lymphocyte density. 32 FLC tumor specimens were analyzed using immunohistochemical staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. 63% of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1+ tumor-infiltrating lymphocytes and tumor-associated macrophages (TILs/TAMs). Myeloid-derived cells appeared to be a major component of PD-L1+ tumor-infiltrating immune cells. 40% of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. IDO and PD-1 expression were highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8+ T-cell density. In conclusion, a high proportion of FLC cases showed robust expression of PD-1, PD-L1, B7-H3, and IDO in an adaptive immune resistance pattern. Our findings provide further basis for targeting these different immune checkpoint axes in FLC.

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