Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress

Abstract

Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.

Prostate Cancer Survivors Present Long-Term, Residual Systemic Immune Alterations

“…Although, in the absence of a suitable control group not treated with radiotherapy it cannot be evaluated with certainty which immune changes are due to radiation effects or due to the malignant condition itself. Within the literature there are very few reports on the long-term follow-up of the immune status of cancer survivors and the detected immune alterations were attributed to both cancer itself and treatment-related long-term consequences [90][91][92].…”

A randomized clinical study on the impact of Comprehensive Geriatric Assessment (CGA) based interventions on the quality of life of elderly, frail, onco-hematologic patients candidate to anticancer therapy: protocol of the ONCO-Aging study

“…Immune senescence is the result of many factors, including tissue damage, DNA damage, chronic inflammation, cell stress, cancer itself and anti-cancer treatments. In this context, an increasing number of T-cells and MDSC with a potential cytotoxic and suppressive activity, has been reported in observations from patients and preclinical data [ 29 ].…”

Senescent T Cells in Age-Related Diseases

“…Immunosenescence leads to a complex and multifaceted decline in innate and adaptive immune functions. The resulting immune dysfunction is instrumental in most biological modifications that occur in the body during physiological aging and age-related diseases, including cardiovascular diseases [13][14][15][16], autoimmune disease [17][18][19][20], cancer [21][22][23], type 2 diabetes [24][25][26], neurodegenerative disease [27][28][29][30], and frailty [10,31]. Moreover, medical treatments that rely on immune function, such as the coronavirus disease 2019 (COVID-19) vaccine, may be less effective in the presence of immunosenescence [32][33][34][35].…”