Multiple immune-suppressive mechanisms in fibrolamellar carcinoma

Amy Kim, Faiz Gani, Andrew J. Layman, Sepideh Besharati, Qingfeng Zhu, Farah Succaria, Elizabeth L. Engle, Feriyl Bhaijee, Maria B. Goggins, Nicolas Llosa, Timothy M. Pawlik, Mark Yarchoan, Elizabeth Jaffee, Howard C. Simons, Janis M Taube, Robert A Anders

Research output: Contribution to journalArticle

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 þ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1 þ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 þ tumor-infiltrating immune cells. Forty percent 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 was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 þ 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.

Original languageEnglish (US)
Pages (from-to)805-812
Number of pages8
JournalCancer Immunology Research
Volume7
Issue number5
DOIs
StatePublished - May 1 2019

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Carcinoma
Neoplasms
Tumor-Infiltrating Lymphocytes
Cytotoxic T-Lymphocytes
Myeloid Cells
Liver Neoplasms
Young Adult
Cell Count
Macrophages
Staining and Labeling
T-Lymphocytes
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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Multiple immune-suppressive mechanisms in fibrolamellar carcinoma. / Kim, Amy; Gani, Faiz; Layman, Andrew J.; Besharati, Sepideh; Zhu, Qingfeng; Succaria, Farah; Engle, Elizabeth L.; Bhaijee, Feriyl; Goggins, Maria B.; Llosa, Nicolas; Pawlik, Timothy M.; Yarchoan, Mark; Jaffee, Elizabeth; Simons, Howard C.; Taube, Janis M; Anders, Robert A.

In: Cancer Immunology Research, Vol. 7, No. 5, 01.05.2019, p. 805-812.

Research output: Contribution to journalArticle

Kim, Amy ; Gani, Faiz ; Layman, Andrew J. ; Besharati, Sepideh ; Zhu, Qingfeng ; Succaria, Farah ; Engle, Elizabeth L. ; Bhaijee, Feriyl ; Goggins, Maria B. ; Llosa, Nicolas ; Pawlik, Timothy M. ; Yarchoan, Mark ; Jaffee, Elizabeth ; Simons, Howard C. ; Taube, Janis M ; Anders, Robert A. / Multiple immune-suppressive mechanisms in fibrolamellar carcinoma. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 5. pp. 805-812.
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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 {\th} cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70{\%} of cases demonstrated PD-L1 {\th} tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 {\th} tumor-infiltrating immune cells. Forty percent 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 was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 {\th} 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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T1 - Multiple immune-suppressive mechanisms in fibrolamellar carcinoma

AU - Kim, Amy

AU - Gani, Faiz

AU - Layman, Andrew J.

AU - Besharati, Sepideh

AU - Zhu, Qingfeng

AU - Succaria, Farah

AU - Engle, Elizabeth L.

AU - Bhaijee, Feriyl

AU - Goggins, Maria B.

AU - Llosa, Nicolas

AU - Pawlik, Timothy M.

AU - Yarchoan, Mark

AU - Jaffee, Elizabeth

AU - Simons, Howard C.

AU - Taube, Janis M

AU - Anders, Robert A

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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 þ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1 þ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 þ tumor-infiltrating immune cells. Forty percent 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 was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 þ 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.

AB - 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 þ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1 þ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 þ tumor-infiltrating immune cells. Forty percent 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 was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 þ 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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