Timeframe: 2016 – 2019
Goal: Define the dominant immune checkpoint pathway in FLC
Principal investigator: Amy K. Kim, MD
Study overview: Tumor cells produce immune checkpoint molecules that suppress host immune response and allow evasion from immune responses. The discovery of drugs that block these immune checkpoints have revolutionized current cancer treatment. Anti-PD1 (programmed cell death protein 1) immunotherapy has shown benefit in many cancer types, but certain cancers have also shown strong resistance to this immunotherapy. At the time of this study, it was unclear how fibrolamellar carcinoma would respond to different immune checkpoint blockades, including anti-PD1 therapy. In addition, it was unclear how circulating tumor cells (CTCs) in the blood that have disseminated from the primary tumor induce anti-tumor immune response outside the tumor environment.
This study aimed to addressed these issues and create a deeper understanding the immune checkpoint landscape in fibrolamellar carcinoma to help guide the development of future immunotherapies. Specifically, this study sought to:
- define the dominant immune checkpoint pathway in fibrolamellar cancer and its interaction with the patient’s immune response in the tumor, and
- determine how immune checkpoint markers are associated with circulating tumor cells in the peripheral blood, in comparison to the primary tumor.
Key findings: The team analyzed thirty-two FLC tumor specimens using immunohistochemistry for the immune checkpoint pathways PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3, in relation to CD8+ cytotoxic T-lymphocyte density. Based on that analysis, 63% of FLC cases demonstrated PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1+ tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Amongst other immune checkpoint pathways, 40% of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8+ T-cell density.
This up regulation of immune checkpoints in FLC is different than in other pediatric cancers and may explain the poor response to checkpoint inhibitor treatment in some cases of FLC. High frequency of PD-L1, IDO, and B7-H3 expression on TILs and TAMs may play an important role in immunosuppression in the TME, which could be targeted for inhibition. Combination of PD-L1 inhibition with either IDO inhibitors or B7-H3–targeted therapy is already in early clinical trials for other solid cancers, so this study provided a rationale for investigating similar approaches in FLC.
Details of the study were published in May 2019 in Cancer Immunology Research. The published article can be read here: https://aacrjournals.org/cancerimmunolres/article/7/5/805/466758/Multiple-Immune-Suppressive-Mechanisms-in
Implications: Data from the study provide further basis for targeting different immune-checkpoint axes in FLC, including combinational treatments.