T cell and Monocyte Specific RNAseq Analysis in Septic and Non Septic Critically-Ill Patients and in Patients with Cancer

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically-ill non-septic (CINS) patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic, CINS, patients with metastatic colon cancer, and healthy controls were analyzed by RNA-seq. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cell than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1 , SOCS-1 , and SOCS-3 , which were highly upregulated in multiple cells types. Multiple negative co-stimulatory molecules including TIGIT , Lag-3 , PD-1 , and CTLA-4 were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders suggesting that immuno-adjuvant therapies that are effective in one disease may also be efficacious in the others.