Liver metastases suppress tumor-specific immunity and contribute to resistance to checkpoint-inhibitor immunotherapies (CPIs), researchers report.
“We found it surprising that tumor presence within the liver can have such a striking influence on the phenotype of tumor-specific CD8 effector T cells at a distant tumor site,” said Dr. James C. Lee of the University of California, San Francisco.
“We also found the highly precise and tumor antigen-specific suppression surprising, but this clued us in on the involvement of a highly sophisticated liver-specific regulatory process,” he told Reuters Health by email.
In malignancies where CPIs have shown efficacy, the presence of liver metastases appears to reduce response rates and survival. It remains unclear how liver metastases modulate systemic antitumor immunity and contribute to CPI resistance.
Dr. Lee and colleagues earlier showed that the presence of liver metastases in patients with melanoma correlated with reduced expression of activation and functional markers on CD8 tumor-infiltrating lymphocytes (TILs) from pre-CPI treatment cutaneous tumor biopsies.
In the current study, they used a preclinical model to examine how the presence of tumor within the liver might influence antitumor immunity at a distant subcutaneous site and explored possible mechanisms leading to CPI resistance.
The presence of tumor in the liver reduced antitumor immunity at the distant tumor site, where lower coexpression of PD-1 and CTLA-4 on cutaneous CD8+ TILs correlated with lower survival and with response rate to anti-PD-1 immunotherapy, they report in Science Immunology.
These effects were independent of tumor burden.