Testicular Cancer Survivors May Have an Immunosenescent Phenotype, Be at Risk for Infections

Testicular Cancer Survivors May Have an Immunosenescent Phenotype, Be at Risk for Infections

A case-control study found that survivors of testicular cancer who underwent chemotherapy have an increased expression of p16INK4a, which has been called a biomarker of aging, in certain immune cells (Abstract 548). Survivors also had variations in T-cell populations that, combined, suggest the presence of an immunosenescent phenotype, researchers said. These results are particularly relevant in view of the finding in a large population-based study that men with testicular cancer who are treated with chemotherapy are more than twice as likely to die of infectious diseases compared to the general population.1

Dr. Maria Teresa Bourlon presents Abstract 548 during Oral Abstract Session B.
“Testicular cancer affects young males between 15 and 35 years old, and cytotoxic chemotherapy can cure patients with advanced disease,” Maria Teresa Bourlon, MD, MS, of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, in Mexico, said at an Oral Abstract Session on urothelial carcinoma and penile, urethral, and testicular cancers on February 9. Previous research has shown an increased expression of p16INK4a after adjuvant therapy for breast cancer, which may be an indicator that therapy is inducing cellular senescence and accelerating molecular aging.

In the course of normal aging, several changes to T lymphocytes, B lymphocytes, and natural killer (NK) cells have been observed; these include reductions in naive T cells CD24+ and CD28+, along with increases in memory T cells and expression of CD57+ cells, among others. These changes can reduce the ability to control infections and diminish the response to vaccines and might increase cancer risk in elderly people. Meanwhile, p16INK4a is a cell-cycle regulating protein and an inhibitor of cyclin-dependent kinases 4 and 6; it is known to play an important role in cellular aging and in premature senescence, Dr. Bourlon said. “The expression of p16INK4a in peripheral blood T cells has been described as a biomarker of aging,” she said.

To study the potential induction of premature immunosenescence in testicular cancer survivors, the investigators conducted a case-control study of 30 individuals. The 15 cases had testicular cancer treated with chemotherapy, and they were matched with 15 healthy controls; p16INK4a expression was measured using real-time polymerase chain reaction, and lymphocyte subpopulations were analyzed using flow cytometry.

The median age of cases was 27 years (range, 24 to 54 years), and there were six cases (40%) of seminoma and nine (60%) of nonseminoma. All patients received at least three cycles of bleomycin, etoposide, and cisplatin (BEP); some received only three cycles (40%), others received four cycles (33.3%), and some received three or four BEP cycles along with paclitaxel, ifosfamide, and cisplatin (TIP) or etoposide, ifosfamide, and cisplatin (VIP). Three patients received radiation therapy (20%), and the median time on surveillance was 26 months.

The analysis showed a significantly higher relative expression of p16INK4a in CD3+ cells in testicular cancer survivors, at 1.30 (relative to glyceraldehyde-3-phosphate dehydrogenase) compared with 0.81 in controls (p = 0.031).

There were also differences with regard to lymphocyte subpopulations. Survivors of testicular cancer had fewer CD4+ cells, at 35% when measured as a proportion of total lymphocytes, compared with 42% in controls (p = 0.013). There were no significant differences with regard to CD8+ cells or NK cells, but survivors had a higher proportion of NK T cells than controls, at 3% compared with 0.9% (p = 0.015). CD19+ cells also did not show a significant difference between the groups.

Dr. Aaron Richard Hansen discusses Abstract 548 during Oral Abstract Session B.
Specifically among CD4+ cells, survivors had a lower proportion of naive CD4+ cells, at 32% compared with 39% (p = 0.041). There was not a significant difference with regard to central memory CD4+ cells, but survivors had a higher proportion of effector memory CD4+ cells, at 18% compared with 9% (p = 0.001).

For CD8+ cells, again there was a higher proportion of naive cells in cases (15%) compared with controls (27%; p = 0.023). There was not a significant difference with regard to either central memory or effector memory CD8+ cells.

An analysis of B lymphocyte subpopulations showed similar proportions of CD19+ cells between the two groups, but a lower proportion specifically of memory B CD19+ cells in survivors, at 17% compared with 27% (p = 0.004). The proportions of plasmablasts were also similar in the two groups.

“There is an immunosenescent phenotype in testicular cancer survivors,” Dr. Bourlon said, adding that this suggests survivors could be at increased risk of infection and reinforces the importance of surveillance in early stages after treatment. She noted that there is still a question of whether these changes will remain stable over time, and that the causal nature of the effect of the chemotherapy versus the cancer itself remains unclear.

Aaron Richard Hansen, MBBS, FRACP, of the Princess Margaret Cancer Centre, in Canada, discussed the abstract and agreed that the tumor itself cannot be excluded as a potential cause of the induced senescence. Although he said this immunosenescent phenotype is “worthy of investigation,” he added that nonchemotherapy causes of senescence were not described in this study; factors such as smoking, physical activity, and type 2 diabetes all could affect senescence, making interpretation of these results is limited. “I think future work in this area must also look at T-cell exhaustion,” he said, which are distinct from senescent T cells in that they can be reversed.

–Dave Levitan