Background
Both hepatocellular cancer and liver metastases are associated with poor clinical outcome and limited therapeutic response to immunotherapy. Tumor antigen specific CD8 T cells in the liver have been studied in the setting of both immunotherapy and cellular therapy with the predominant dogma that these cells have equivalent functionality in the liver as compared to other organ sites. Herein, we detail that tumor antigen specific or potentially tumor reactive CD 8 T cells are uniquely nonfunctional in the liver immune microenvironment in both mice and humans. 
Methods
Both a colon cancer line (CT26) and a melanoma model (B16F10) were injected intrahepatically, into the tail vein, and subcutaneously in BALB/c and C57BL/6 mice to create liver, pulmonary and subcutaneous tumors respectively. CD8 T cells were depleted by ⍺CD8 treatment. Liver and tumor infiltrating immune cells and splenocytes were analyzed by flow cytometry. Peptide loaded tetramers were used to identify antigen-specific T cells and tumor growth was monitored. Additionally, publically available single cell RNA sequencing data from 10 patient samples with primary colon cancer and liver metastasis were used. Human single cell data was analyzed using the Seurat pipeline and single cell gene enrichment analysis in R. 
Results
Both in mice and humans, a higher frequency of tumor antigen specific or potentially tumor reactive CD8 T cells was found in the liver as compared to other organ sites. Additionally, a higher frequency of these were found to be exhausted in the liver (TIM3+ and CD39+ in mice and an exhausted cluster similarly defined in humans). Surprisingly, CD8 T cell depletion had no effect on tumor growth in the liver while depletion caused tumor growth in the subcutaneous model. Additionally, through Cell Chat analysis, SPP1 positive macrophages were found to be key mediators of this exhausted phenotype and these interactions were enriched in the liver. 
Conclusion
Tumor reactive CD8 T cells are found at significantly higher frequency in the liver. Despite the higher frequency of “killer” T cells in the liver, tumor growth in the liver was not impacted by tumor reactive CD8 T cells in contrast to subcutaneous tumors, which were smaller in the presence of tumor-specific T cells. Spp1+ macrophages seem to be key mediators in tumor reactive CD8 T cell dysfunction uniquely in the liver. These findings may explain the poor clinical response seen in these patients as well as present as a potentially target for therapeutic affects.

Macrophage-Mediated Hepatic Dysfunction Impairs Tumor Antigen-Specific CD8+ T Cell Function in the Liver

 Hematology / Oncology / Pathology

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Macrophage-Mediated Hepatic Dysfunction Impairs Tumor Antigen-Specific CD8+ T Cell Function in the Liver

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