Aging-related biomarkers in testicular cancer survivors after different oncologic treatments

Abstract

Purpose: Testicular cancer survivors (TCS) exposed to chemotherapy have an increased expression of CDKN2A/p16^INK4a and a lymphocyte phenotype associated with immunosenescence. We seek to define whether the immunosenescent phenotype is associated with chemotherapy.

Methods: Case-control study of TCS, disease-free ≥3 months and stratified by primary treatment modality into orchiectomy only, chemotherapy, or bone marrow transplant (BMT). Each group was compared with age-matched healthy controls (HC). We measured the relative proportions of lymphocyte subpopulations using flow cytometry, levels of C-reactive protein, and relative expression of CDKN2A/p16^INK4a quantified by qPCR.

Results: We included 65 patients; 19 were treated with orchiectomy only, 35 received different doses of chemotherapy, and 11 underwent BMT. The chemotherapy and BMT groups had decreased naïve CD4 cells compared to HC. The chemotherapy group showed increased central and effector memory CD4 cells, as well as effector and terminally differentiated CD8 cells, compared to HC. Chemotherapy (chemotherapy 1.84 vs. HC 0.92; p < 0.01) and BMT (BMT 6.96 vs. HC 1.25; p < 0.005) groups had higher expression of CDKN2A/p16^INK4a compared to HC. The orchiectomy group showed no significant difference with HC (orchiectomy 1.73 vs. HC 1.01; p = 0.17). CRP levels were higher in all groups when compared with HC; in the orchiectomy group, they were only marginally increased (chemotherapy 0.22 vs. HC 0.06; p < 0.01; BMT 0.26 vs. HC 0.06; p < 0.01; orchiectomy 0.09 vs. HC 0.07; p < 0.01).

Conclusions: Among TCS, only patients exposed to cytotoxic agents developed an immunosenescent phenotype. This finding supports the attribution of this alteration to the cytotoxic treatment.

Keywords: biomarkers; cancer care continuum; chemotherapy; germ cell tumor; survival.

FIGURE 1

Differences in CD4 and CD8 populations across groups. Determination of CD4⁺ and CD8⁺ cell counts (cells/μL) across groups.

FIGURE 2

C reactive protein and CDKN2A/p16 ^INK4a values in different groups. Determination of C reactive protein levels (mg/dL) across treatment groups.

FIGURE 3

Linear regression for age and CDKN2A/p16 ^INK4a . Linear regression demonstrating CDKN2A/p16 ^INK4a values across groups.

FIGURE 4

The difference in values of CDKN2A/p16 ^INK4a between groups. There is a significant difference in values of CDKN2A/p16 ^INK4a between groups.

FIGURE 5

Primary components analysis of cellular populations that showed significant differences between groups. Primary components analysis shows the distribution of cellular populations with significant differences between groups.