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Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination
Jiali Yu1,2, Michael D Green3,4,5, Shasha Li1,2,6
1Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
Insights
Liver metastases reduce immunotherapy effectiveness by depleting CD8+ T cells. Liver-directed radiotherapy combined with immunotherapy may enhance systemic anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Metastasis to the liver is a common cause of cancer mortality.
- The role of liver immune tolerance in cancer outcomes remains unclear.
- Liver metastases may impact systemic immunotherapy efficacy.
Purpose of the Study:
- To investigate the impact of liver metastases on systemic immunotherapy efficacy.
- To elucidate the mechanisms by which liver metastases affect T cell populations.
- To explore potential therapeutic strategies combining radiotherapy and immunotherapy.
Main Methods:
- Analysis of patient data on immunotherapy response and liver metastases.
- Preclinical studies in mouse models of liver metastases.
- Flow cytometry to analyze T cell populations (CD8+, Fas+, FasL+).
- Assessment of macrophage populations (CD11b+, F4/80+).
- Evaluation of the effects of liver-directed radiotherapy.
Main Results:
- Liver metastases significantly diminish systemic immunotherapy efficacy in patients and mouse models.
- Liver metastases cause activated CD8+ T cells to be siphoned from circulation.
- In the liver, Fas+CD8+ T cells undergo apoptosis via interaction with FasL+ macrophages.
- This leads to a systemic reduction in T cell numbers, diversity, and function.
- Liver-directed radiotherapy reduced immunosuppressive macrophages and T cell siphoning.
Conclusions:
- Liver metastases induce acquired immunotherapy resistance by promoting CD8+ T cell deletion.
- Liver metastases exploit host peripheral tolerance mechanisms.
- Combining liver-directed radiotherapy with immunotherapy shows promise for enhancing systemic anti-tumor immunity.
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