A Proposed Link Between Acute Thymic Involution and Late Adverse Effects of Chemotherapy

Abstract

Epidemiologic data suggest that cancer survivors tend to develop a protuberant number of adverse late effects, including second primary malignancies (SPM), as a result of cytotoxic chemotherapy. Besides the genotoxic potential of these drugs that directly inflict mutational burden on genomic DNA, the precise mechanisms contributing to SPM development are poorly understood. Cancer is nowadays perceived as a complex process that goes beyond the concept of genetic disease and includes tumor cell interactions with complex stromal and immune cell microenvironments. The cancer immunoediting theory offers an explanation for the development of nascent neoplastic cells. Briefly, the theory suggests that newly emerging tumor cells are mostly eliminated by an effective tissue immunosurveillance, but certain tumor variants may occasionally escape innate and adaptive mechanisms of immunological destruction, entering an equilibrium phase, where immunologic tumor cell death “equals” new tumor cell birth. Subsequent microenvironmental pressures and accumulation of helpful mutations in certain variants may lead to escape from the equilibrium phase, and eventually cause an overt neoplasm. Cancer immunoediting functions as a dedicated sentinel under the auspice of a highly competent immune system. This perspective offers the fresh insight that chemotherapy-induced thymic involution, which is characterized by the extensive obliteration of the sensitive thymic epithelial cell (TEC) compartment, can cause long-term defects in thymopoiesis and in establishment of diverse T cell receptor repertoires and peripheral T cell pools of cancer survivors. Such delayed recovery of T cell adaptive immunity may result in prolonged hijacking of the cancer immunoediting mechanisms, and lead to development of persistent and mortal infections, inflammatory disorders, organ-specific autoimmunity lesions, and SPMs. Acknowledging that chemotherapy-induced thymic involution is a potential risk factor for the emergence of SPM demarcates new avenues for the rationalized development of pharmacologic interventions to promote thymic regeneration in patients receiving cytoreductive chemotherapies.

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

“…Among thymic disorders, age-dependent involution is the most well-characterized thymic pathology 120 , and as such, served as the primary focus for demonstrating our pipeline's utility. Additionally, the thymus is vulnerable to acute involution 9,121,122 , from factors like chemo/radiotherapy 123 , infections 121 , sexual steroids 124,125 , pregnancy 126,127 , and obesity 32,128 . Therefore, our pipeline may be utilized to offer insights in studies aimed at dissecting the molecular mechanisms and reversing thymic involution.…”

Comprehensive characterization of the T cell receptor repertoire in bladder cancer

“…The reduced TCR diversity and lymphocyte count are likely caused by cytotoxic cisplatin chemotherapy. While highly effective against cancer cells, cisplatin may cause degradation of the thymus 34 , causing reduced production of naive T cells with potentially detrimental effects on long-term patient health 35 . Conversely, for patients with early-stage bladder cancer, we found that patients with good outcomes after BCG showed an increase in TCR diversity.…”