ASCO GU 2018: Collateral damage: Molecular aging and p16INK4a senescence protein in testicular cancer survivors treated with chemotherapy

San Francisco, CA ( Testicular cancer most commonly affects young men between the ages of 15-35.  While cytotoxic chemotherapy is commonly used as a very effective treatment for many men with testicular malignancies, there are both short-term and long-term side effects of this treatment.  One such long-term side effect of undergoing chemotherapy is an increased risk of developing a secondary malignancy later in life. 

During the Testicular Cancer Oral Abstract Session at the 2018 Genitourinary Cancers Symposium, Dr. Maria Bourlon presented a translational research project which was developed to better understand what effects that cytotoxic chemotherapy has on the immune system.  It has been previously shown that cancer treatment can induce cellular senescence and may accelerate molecular aging. P16INK4a is one biomarker of cellular aging that has been shown to change after treatments for other malignancies, such as breast cancer.  This is a cell-cycle regulating protein that inhibits cyclin-dependent kinases 4 and 6 and has an important role in cellular aging and premature senescence. It has been hypothesized that systemic chemotherapy may increase P16INK4a expression through unknown mechanisms and subsequently lead to cell aging. This may have implications for the development of secondary medical conditions later in life, including the development of secondary malignancies, as the immune system plays a role in the development of cancer. 

In order to determine the effect that cytotoxic chemotherapy has on lymphocyte subpopulations and phenotypes, as well as to study chemotherapy's effect on p16INK4a expression, Dr. Bourlon and colleagues enrolled men who had previously been treated with at least 3 cycles of bleomycin, etoposide, and cisplatin-based chemotherapy and compared them to a cohort of 15 healthy age-matched men who had never previously received chemotherapy.  Blood samples were obtained from all participants and lymphocyte subpopulation levels were evaluated.

They found that men who had previously received chemotherapeutic agents had statistically lower levels of CD4+ cells, as well as higher levels of natural killer T cells. Men treated for testicular cancer additionally had lower levels of naive CD4+ cells and higher levels of effector memory CD4+ cells.   Furthermore, they found that there was a statistically higher p16INK4a expression in men who had previously undergone chemotherapy as compared to the matched controls (p = 0.031).

Based on their data showing multiple differences in the levels of immune cell subpopulations and p16INK4a expression, they concluded that there appears to be evidence of an immunosenescent phenotype in men who have previously received chemotherapy for the treatment of testicular cancer.  They believe that further studies are required to help elucidate the clinical implications of this immunosenescence. 

Presented by: Maria Bourlon, MD, MS

Written by: Brian Kadow, MD, Fox Chase Cancer Center, Philadelphia, PA  2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA