Immunosenescence Profile and Expression of the Aging Biomarker (p16INK4a) in Testicular Cancer Survivors Treated with Chemotherapy - Beyond the Abstract

Testicular cancer is one of the most curable solid malignancies, even in advanced stages. However, the high cure rate among testicular cancer survivors (TCS) is offset by the long-term toxicity of oncologic treatments which include second malignant neoplasms, hypogonadism, pulmonary toxicity, and nephrotoxicity. Compared to the normal population, TCS have an increased risk of dying from circulatory diseases and infections. Such risk is particularly greater in patients who received chemotherapy.1



Elderly people are at high risk of developing cancer and have a decreased ability to control infections. These complications are greatly caused by immunosenescence, the aging process of the immune system. Immunosenescence is characterized by several changes in the lymphocyte subpopulations: there is a decrease in T cells and naïve lymphocytes (B and T cells), while CD57+ and CD28- terminally differentiated senescent cells increase. The cell-cycle regulating protein p16INK4a is also a senescence biomarker; its expression in most tissues increases with cellular aging.2

Cytotoxic chemotherapy can induce cellular senescence in normal and cancer cells.3 Therefore, we hypothesized that TCS have premature immunosenescence, which may explain the aforementioned long-term complications. This pilot study aimed to search for lymphocyte senescence surface markers as well as p16INK4a gene expression among TCS who were given chemotherapy.4

Our team conducted a case-control study of TCS matched by age and gender with healthy controls. We included patients with at least three bleomycin, etoposide, and cisplatin (BEP) chemotherapy cycles and no evidence of disease for at least three months. Patients with high-dose chemotherapy were excluded. Peripheral blood mononuclear cells were isolated and lymphocyte subpopulations were analyzed by flow cytometry. B and T cells and their corresponding naïve and memory subpopulations were defined according to their surface marker combinations. p16INK4a gene expression in T cells was measured using quantitative polymerase chain reaction.

We found that TCS who had previously received chemotherapeutic agents had statistically significant lower levels of total T cells and CD4+ T cells. Among the CD4+ T lymphocytes, TCS had less naïve and increased effector memory cells. Within the CD8+ T lymphocytes, TCS exhibited a decrease in the percentage of naïve cells and an increase in CD45RA + CD57+ cells (surface markers related to the later stages of differentiation). Furthermore, we found that there was a statistically significant higher p16INK4a gene expression in TCS as compared to the matched controls. These differences are highlighted in Figure 1.

Immunosenesce profile of Testicular Cancer Survivors TCS compared with Healthy Controls
Figure 1. Immunosenescence profile of testicular cancer survivors (TCS) compared with healthy controls.

Our data suggest that TCS previously treated with chemotherapy may have an immunological phenotype associated with immunosenescence. Potential confounders for these results (like diabetes and hypogonadism) were controlled and excluded. Chemotherapy’s causal effect, however, remains to be defined. Our study has several limitations, the most important being the cross-sectional nature of it, and we do not know if these alterations persist over time. Future evaluations are necessary to be done in a longitudinal study that allows a patient’s evaluation at diagnosis, during, and after oncologic
treatments.

We believe that further studies are required to help elucidate the clinical implications of the premature immunosenescence in TCS. This is a group of patients that warrants special attention for they receive oncologic treatments at a very young age, and premature immunosenescence may impose many consequences during their lifespan.

Written by: Maria T Bourlon, MD, MSc, Twitter: @BourlonMaite, Francisco J Castro-Alonso, MD, Arturo Carballo, MD, Luis Llorente, MD, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

References:

  1. Fosså, Sophie D., Ethel Gilbert, Graça M. Dores, Jinbo Chen, Katherine A. McGlynn, Sara Schonfeld, Hans Storm et al. "Noncancer causes of death in survivors of testicular cancer." Journal of the National Cancer Institute 99, no. 7 (2007): 533-544.
  2. Xu, Weili, and Anis Larbi. "Markers of T cell senescence in humans." International journal of molecular sciences 18, no. 8 (2017): 1742.
  3. Ewald, Jonathan A., Joshua A. Desotelle, George Wilding, and David F. Jarrard. "Therapy-induced senescence in cancer." JNCI: Journal of the National Cancer Institute 102, no. 20 (2010): 1536-1546.
  4. Bourlon, Maria T., Hugo E. Velazquez, Juan Hinojosa, Luis Orozco, Ricardo Rios-Corzo, Guadalupe Lima, Luis Llorente et al. "Immunosenescence profile and expression of the aging biomarker (p16 INK4a) in testicular cancer survivors treated with chemotherapy." BMC cancer 20, no. 1 (2020): 1-7.
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