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Published on: November 28, 2019
Liver Metastasis Modulate Responses of Suppressive Macrophages and Exhausted T Cells to Immunotherapy Revealed by
Qiming Zhang1,2,3, Siyuan Liu4, Yedan Liu1,2
1Beijing Advanced Innovation Center for Genomics (ICG) School of Life Sciences Peking University Beijing 100871 China.
Abstract:
Liver metastasis is associated with immunotherapy resistance, although the underlying mechanisms remain incompletely understood. By applying single cell RNA-sequencing to a concurrent subcutaneous and liver tumor murine model to recapitulate liver metastases, it is identified that subsets within tumor-infiltrating exhausted CD8+ T (Tex) cells and immunosuppressive tumor-associated macrophages (TAMs) display opposite responses to concurrent liver tumors and anti-PD-1 treatment, suggesting a complex immune regulating network. Both angiogenic and interferon-reactive TAMs show increased frequencies in implanted liver tumors, and anti-PD-1 treatment further elevates the frequencies of angiogenic TAMs. Such TAMs frequencies negatively correlate with the proportions of cytotoxic T cell subsets. Further, expression of interferon-stimulated genes in TAMs is dramatically reduced under effective anti-PD-1 treatment, while such tendencies are diminished in mice with implanted liver tumors. Therefore, the study indicates that liver metastases could increase immunosuppressive TAMs frequencies and inhibit Tex responses to PD-1 blockade, resulting in compromised systemic antitumor immunity and limited immunotherapy efficacy.
Insights
Liver metastases worsen immunotherapy resistance by increasing immunosuppressive tumor-associated macrophages (TAMs) and hindering exhausted CD8+ T cell (Tex) responses to anti-PD-1 treatment, compromising antitumor immunity.
Area of Science:
- Immunology
- Oncology
- Translational Medicine
Background:
- Liver metastasis is a significant challenge in cancer therapy, often linked to resistance to immunotherapy.
- The precise immunological mechanisms driving this resistance, particularly concerning T cells and macrophages, are not fully elucidated.
Purpose of the Study:
- To investigate the impact of liver metastases on the tumor microenvironment and immune cell responses during anti-PD-1 therapy.
- To identify specific immune cell subsets and their interactions that contribute to immunotherapy resistance in the context of liver metastasis.
Main Methods:
- Utilized a murine model with concurrent subcutaneous and liver tumors to simulate liver metastases.
- Employed single-cell RNA sequencing to analyze tumor-infiltrating exhausted CD8+ T cells (Tex) and tumor-associated macrophages (TAMs).
- Assessed the effects of anti-PD-1 treatment on these immune cell populations.
Main Results:
- Liver metastases altered TAM subsets, increasing angiogenic and interferon-reactive TAMs, with anti-PD-1 further boosting angiogenic TAMs.
- Elevated TAM frequencies correlated with reduced cytotoxic T cell populations.
- Anti-PD-1 treatment diminished interferon-stimulated gene expression in TAMs, an effect blunted by liver tumors.
Conclusions:
- Liver metastases promote immunosuppressive TAMs and impair exhausted T cell responses to PD-1 blockade.
- These immune dysregulations compromise systemic antitumor immunity, leading to reduced immunotherapy efficacy.
- Understanding these mechanisms is crucial for developing strategies to overcome immunotherapy resistance in metastatic cancer.
