In this issue of Blood Advances, Kooshesh et al1 found that cancer, not cardiovascular disease, underlies the increased mortality after thymectomy in a follow-up cause of death analysis of data from their earlier study showing increased overall mortality and cancer incidence in adults who had undergone thymectomy.2 Despite substantial age-related involution and decline in thymic T-cell output, the thymus continues to produce new T cells for the first 5.5 decades of life.3 Although thymectomy is a frequent part of cardiac surgery in both children and adults, the long-term clinical impact of thymus removal is poorly defined. Moreover, outcome data analyzed in the context of the age at which the thymus was removed could reveal key insights about the functional significance and the specific immunoregulatory contributions (immunity vs tolerance) of thymic activity in adulthood.
Immune profiling studies indicate a proinflammatory milieu with an immunosenescence-like T-cell phenotype after thymectomy2,4; the central role of inflammation in the genesis and pathogenic consequences of atheromas5 raises the question of whether thymectomy heightens the risk for atherosclerotic cardiovascular late effects. Kooshesh et al address this question via a retrospective case-control analysis. A comparative single institution analysis of >1500 patients who underwent thymectomy in adulthood over a 27-year period and 5 times as many control individuals who received care at the same institution and had been matched for demographic and key cardiovascular risk factors revealed twofold 5-year mortality and cancer incidence rates in patients who underwent thymectomy. However, the rates of major cardiovascular events, including those requiring procedural intervention, did not differ between the two groups; the cardiovascular event risk in patients who underwent thymectomy was similar to that seen in the general US population. Notably, the distribution of cancer types by tissue among those who died differed between the 2 groups, and the cancer relapse rate among those who died was higher in the thymectomy group. In addition to replicating the cancer and mortality risk data reported in their earlier study with a different control cohort, the current study provides valuable cardiovascular-specific data for late effects risk counseling of patients requiring thymectomy. Multicenter studies are needed to confirm these findings and assess for ethnicity-based differences in late effect risks after thymectomy. Given the retrospective study design, it is unknown whether the observed increase in cancer incidence and recurrence rates represents an effect of thymectomy or a higher cancer predisposition in those with clinical conditions necessitating thymectomy. A T-cell phenotype reminiscent of accelerated immune aging has been reported after thymectomies were performed in both children and adults.2,4 This senescence-like phenotype of the T-cell pool after thymectomy is marked by a drop in naïve T-cell production, increased fraction of memory cells in both the conventional and regulatory T-cell compartments, reduced T-cell receptor (TCR) diversity, and shorter telomeres.6 Similarly, mice who underwent thymectomy as young adults show a drop in naïve T-cell numbers, increased proliferation of existing blood T cells, and accelerated accumulation of PD1+ T cells that transcriptionally resemble the hypofunctional senescent T cells with upregulated expression of inflammation genes normally seen in aged mice.7 Consistent with the increased expression of proinflammatory genes observed in T cells in thymectomized and aged mice, a proinflammatory plasma cytokine profile marked by increased type 2 and type 17 helper T-cell cytokines was seen in patients with a history of adult thymectomy.2 Overall, possible mechanisms underlying thymectomy-associated cancers include decreased cancer immunosurveillance (secondary to reduced functionality and TCR repertoire contraction of the T-cell pool), and inflammation-driven tumor development and progression.8 Increased risk for cancer has not been reported after thymectomy in childhood; however, outcome data for childhood thymectomy are limited to small studies with limited follow-up. The increased cancer risk in the setting of immunosenescence after thymectomy in adulthood provides rationale for the systematic investigation of long-term risks in children undergoing thymectomy. Prospective case-control cohort studies that characterize the baseline cancer predisposition risk via genomic profiling and comprehensive cancer risk data collection and assess baseline and serial immune profiles after surgery, as well as animal model studies to investigate plausible biological mechanisms underlying the link between thymectomy and cancer, are needed to determine causation vs correlation. Such studies have the potential to yield insights that enable risk-benefit determination for thymectomy, define the function of the thymus in adulthood, and reveal immunosenescence mechanisms that can be therapeutically targeted in cancer.
Conflict-of-interest disclosure: C.P. declares no competing financial interests.
