Immune Activation, Exhaustion and Senescence Profiles as Possible Predictors of Cancer in Liver Transplanted Patients

Abstract

Liver transplanted (LT) patients for hepatocellular carcinoma (LT-HCC) or for other causes (LT-no-HCC) may develop post-transplantation malignancies. Although immune activation and senescence are frequently implicated in cancer development, no data is available on their possible role as biomarkers predictive of tumor onset in this setting. A total of 116 patients were investigated: the 45 LT-HCC patients were older than the 71 LT-non-HCC (p=0.011), but comparable for sex, HCV, HBV infection and immunosuppressive treatment. At baseline, the numbers of activated and senescent-like circulating cells were significantly higher in LT-HCC patients than in LT-no-HCC ones. After a median follow-up of 26.8 months, 6 post-transplant malignancies (PTM) occurred: 4 in LT-HCC (8.9%) and 2 in LT-no-HCC (2.8%) patients. Overall, subjects with high percentages of activated and exhausted T and B cells at baseline were at higher risk of PTM. Notably, within the LT-HCC group, a higher percentage of senescence-like T cells was also associated with cancer development. Moreover, patients with PTM had higher telomere erosion and higher levels of circulating PAMPs (16S rDNA) and DAMPs (mtDNA) when compared with matched patients without PTM. Overall, these findings suggest that immune activation and exhaustion may be useful to predict the risk of PTM occurrence, regardless of the cause of transplantation. In LT-HCC, T-cell senescence represents an additional risk factor for tumor onset.

Keywords: biological predictors; hepatocellular carcinoma; immune activation; immune senescence; post-transplant malignancy.

Figure 1

Baseline immune activation, exhaustion and senescence profiles in LT-HCC and LT-no-HCC patients. Percentages of (A) activated CD8⁺ (CD3⁺CD8⁺CD38⁺HLA-DR⁺), CD4⁺ (CD3⁺CD4⁺CD38⁺HLA-DR⁺) and memory B (CD19⁺CD10^-CD21^-CD27⁺) cells; (B) exhausted CD8⁺ (CD3⁺CD8⁺PD-1⁺), CD4⁺ (CD3⁺CD4⁺PD-1⁺) and B (CD19⁺PD-L1⁺) cells, (C) senescent-like CD8⁺ (CD3⁺CD8⁺CD28^-CD57⁺), CD4⁺ (CD3⁺CD4⁺CD28^-CD57⁺), and B (CD19⁺CD27^-IgD^-) cells in LT-HCC and LT-no-HCC patients. All p-values were adjusted by age.

Figure 2

Baseline immune activation, exhaustion and senescence profiles in LT-PTM and LT-no-PTM patients. Percentages of (A) activated CD8⁺ (CD3⁺CD8⁺CD38⁺HLA-DR⁺), CD4⁺ (CD3⁺CD4⁺CD38⁺HLA-DR⁺) and memory B (CD19⁺CD10^-CD21^-CD27⁺) cells; (B) exhausted CD8⁺ (CD3⁺CD8⁺PD-1⁺), CD4⁺ (CD3⁺CD4⁺PD-1⁺) and B (CD19⁺PD-L1⁺) cells, (C) senescent-like CD8⁺ (CD3⁺CD8⁺CD28^-CD57⁺), CD4⁺ (CD3⁺CD4⁺CD28^-CD57⁺), and B (CD19⁺CD27^-IgD^-) cells in LT-PTM and LT-no-PTM patients. All p-values were adjusted by age.

Figure 3

Circulating markers of microbial translocation between LT-PTM and mLT-no-PTM at baseline and follow-up. Circulating levels of (A) PAMPs (16S rDNA) and (B) DAMPs (mtDNA) in LT-PTM versus mLT-no-PTM patients at baseline and follow-up.