"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.
The presence of tumor cells in the liver did not appear to alter the generation and expansion of CD8 T cells, but there was a significant reduction in the expression of functional markers on the tetramer+ CD8 T cells within the subcutaneous tumor.
This dysfunctional state was not reversed by anti-PD-1 treatment despite the high expression of PD-1 on these T cells, suggesting that T cell exhaustion through the PD-1 axis was unlikely to be the main mechanism involved in immune suppression of the antitumor response.
Depletion of regulatory T cells (Tregs), however, restored the activation and functional status of tumor-specific CD8 T cells, suggesting that Tregs play a critical role in modulating these distant effects.
Additional experiments indicated that the combination of checkpoint blockade with the depletion or disruption of Treg function might enhance durable antitumor immunity in the presence of liver metastases where CPI monotherapy proves ineffective.
High-dimensional profiling of innate immune cells in the tumor microenvironment further suggested that immunosuppression driven by the presence of liver metastases could be a consequence of crosstalk between Treg and myeloid-derived suppressor cells.
"The data raises the possibility that liver-metastasis-directed therapies, such as liver-targeted radiation or surgery, in the metastatic setting, may add benefit to PD-1 blockade (i.e., producing an abscopal effect), since we found the origin of the mechanisms of systemic suppression to be from the liver," Dr. Lee said. "If tested to be true in further studies, it would challenge the current therapeutic paradigm and dogma in oncology, which is to not provide these treatments to specific metastatic states in a widely metastatic patient."
"Our results suggest we could benefit from the ability to use readily available clinical features, such as presence of liver metastasis, to more precisely deploy the more intensive (with potentially more side effects, and higher cost to society) combination immunotherapies to just the patients that truly need it," he said. "Larger human studies are needed to validate ours in patients, and biomarkers should be developed."
"When in place, precision immunotherapy can theoretically be deployed/triaged to be deployed in intelligently selected patients," Dr. Lee said. "Then we have the potential to avoid unnecessary immune-related adverse events (irAEs) and minimize the associated cost to society."
By Will Boggs MD
SOURCE: https://bit.ly/3jG07OO Science Immunology, online October 2, 2020.
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