Scientific Publications and Presentations

Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD‑1 and IL‑10 blockade

March 1, 2024

Daniel, Sullivan, Dickerson, ... , Riehle, Yeung, Carter, Barry & Pillarisetty
Journal article published in Nature Scientific Reports

Due to limited knowledge about the immune response to FLC, developing effective immunotherapy is challenging for the disease. In this study, the team investigated the immune environment of fibrolamellar carcinoma (FLC) using several techniques including multiplex immunohistochemistry and flow cytometry.

Key findings of the effort include:

  • Immune cells are largely sequestered away from tumor cells in FLC. Instead, they are most often found in nearby non-tumor liver tissue and the dense fibrous bands within the tumor (after which FLC is named).
  • These tumor-infiltrating lymphocytes (TILs) often show signs of exhaustion and lack activation markers compared to T cells in the surrounding liver tissue.
  • T cells in fibrolamellar carcinoma (FLC) showed low levels of clonal expansion, even though similar T cell receptor (TCR) sequences existed across different patients. This high similarity in TCR sequences across patients suggests that T cells in FLC tumors could be enriched with TCRs that may recognize common neoantigens to FLC. However, the immunosuppressive nature of the FLC tumor environment may be limiting the effectiveness and expansion of these tumor-specific T cells. The team hypothesized that if the suppressive environment within FLC tumors could be reversed, these specific T cells could be activated to effectively kill the tumor cells.
  • An immune signaling protein (cytokine) named interleukin-10 (IL-10) can suppress the immune response against FLC cancer cells. IL-10 is generally known as an anti-inflammatory factor. While in many situations limiting inflammation is desirable, in this case IL-10 may prevent anti-FLC immune cells from reaching the cancer cells they are programmed to kill. Using lab cultures of slices cut from fresh FLC tumors, they then found that blocking IL-10, combined with blocking the immune checkpoint PD-1, can free killer T cells from the stroma and enable a more potent immune response against FLC cells in several, but not all the cultures.

Implications: The key takeaway of this study is that blockade of cytokine signaling in combination with immune checkpoints, potentially offers a new way to enable anti-FLC immune cells to kill FLC cancer cells more effectively. The study also highlights the importance of further work focused on better understanding the complex interactions between immune, chemokine, stromal, and metabolic factors in FLC’s tumor microenvironment that affect immune cell infiltration and function.

The full text of the study can be read here.

Note: The study underlying this publication was partially funded by FCF. Lindsay Dickerson, a co-author on the study, is an active FCF-CRI fellow.