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Published on: January 3, 2013
The potential application of PD-1 blockade therapy for early-stage biliary tract cancer
Kumiko Umemoto1,2, Yosuke Togashi1, Yasuhito Arai3
1Division of Cancer Immunology, Research Institute, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
Abstract:
Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.
Insights
Programmed cell death-1 (PD-1)+ CD8+ T cells are crucial for anti-tumor immunity in biliary tract cancer (BTC). Their presence in early-stage BTC suggests potential efficacy of PD-1 blockade therapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Biliary tract cancer (BTC) exhibits aggressive behavior and limited therapeutic options, including immunotherapies.
- Programmed cell death-1 (PD-1) blockade therapy shows suboptimal efficacy in BTC, highlighting the need to understand its tumor microenvironment (TME).
Purpose of the Study:
- To investigate the immunological status of the TME in BTC, focusing on PD-1+ CD8+ T cells.
- To correlate the presence and location of PD-1+ CD8+ T cells with BTC stage and response to PD-1 blockade therapy.
Main Methods:
- Analysis of the TME immunological status in 37 BTC samples across different disease stages.
- Utilizing imaging mass cytometry to examine the spatial distribution of PD-1+ CD8+ T cells and PD-1- CD8+ T cells.
- Employing a mouse model to assess the impact of tumor growth on PD-1 expression and PD-1 blockade therapy response.
Main Results:
- PD-1+ CD8+ T cells were abundant in early-stage BTC and diminished with disease progression.
- Tumor-infiltrating PD-1+ CD8+ T cells were located near tumor cells, while PD-1- CD8+ T cells were found in the stroma.
- In a mouse model, smaller tumors with higher PD-1+ CD8+ T cell expression were sensitive to PD-1 blockade, whereas larger tumors were resistant.
Conclusions:
- Tumor-infiltrating PD-1+ CD8+ T cells play a significant role in anti-tumor immunity within the BTC TME.
- Early-stage BTC with higher PD-1+ CD8+ T cell infiltration may benefit from PD-1 blockade therapy.
