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. 2022 Jul 1:13:933547.
doi: 10.3389/fimmu.2022.933547. eCollection 2022.

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

Maria K Lagou  1   2 , Dimitra P Anastasiadou  1   2 , George S Karagiannis  1   2   3   4   5
Affiliations

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

Maria K Lagou et al. Front Immunol. .

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.

Keywords: T cell; cancer immunoediting theory; chemotherapy; immune surveillance; second primary malignacies; thymic involution.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Proposed Link Between Acute Thymic Involution and Development of Second Primary Malignancy. In the absence of exposure to prior treatments with cytoablative chemotherapies due to a first-primary tumor (upper half of illustration), the emergence of nascent transformed cells is subjected to a “competent” cancer immunoediting process. At the beginning, the competent immune system can eliminate neoplastic cells via an efficient immune surveillance machinery. Then tumor cell growth is balanced by immunogenic cell death, described as equilibrium phase. And finally, immunosculpting leads to the escape phase, during which anticancer immunity fails to control tumor growth and creates a clinically overt tumor. The succession of these three phases is a long-lasting process with two main contributing factors: First, genomic instability is increased over time, leading to accumulation of driver mutations and genetic diversity that allows immunoevasive and immunosuppressive mechanisms to evolve (e.g. development of tumor cell clones with absent or low immunogenicity). At the same time, age-related thymic involution causes a decreased T cell peripheral pool and T cell receptor repertoires, leading to failure of immune surveillance and equilibrium mechanisms. In contrast, following exposure to a first-primary tumor and associated treatment with cytoreductive chemotherapy (lower half of illustration), the failure of the immune surveillance and equilibrium mechanisms occurs at a much earlier timepoint, allowing for the onset of clinically overt second primary malignancies (SPMs) at a younger age, compared to first-primary tumors (compare timelines between upper and lower half of illustration). Contributing factors for the SPM are the genotoxic nature of cytotoxic chemotherapy (which grants genomic instability and mutational burden at a very early onset), and chemotherapy-induced acute thymic involution causing impaired thymopoiesis, T cell receptor repertoires, and peripheral T cell pools, thus weakening immune surveillance mechanisms during elimination and equilibrium phases. Relative thickness of gray bars underneath the timelines in each condition indicates the strength of thymopoiesis (upper bar), and genomic instability (lower bar) over time (not drawn to scale). Illustration designed with Biorender.
Figure 2
Figure 2
Modes of Thymic Epithelial Cell Death After Chemotherapy Treatment. (A) Cytoreductive chemotherapy non-specifically and unconditionally targets proliferation niches in the entire organism, and as such, insults TEC subsets in the act of cell division. (B) Cytoreductive chemotherapy suppresses bone marrow hematopoiesis and subsequent early thymocyte progenitor homing in the thymic microenvironment, thus disrupting thymocyte-derived prosurvival signals essential for TEC homeostasis, and causing “attritional” cell death to sensitive TEC subsets (e.g., AIRE+ mTEC). Illustration designed with Biorender.
Figure 3
Figure 3
Strategies for Enhancing Thymus Regeneration Following Chemotherapy. (A) Examples of thymus regeneration strategies targeting thymic stromal cell networks activated in endogenous thymic repair. (B) Examples of thymus regeneration strategies targeting negative feedback loops on thymus size/function from sex hormones. (C) Examples of thymus regeneration strategies involving the transplantation of (pre-conditioned) bone marrow-derived thymocyte progenitors. (D) Examples of thymus regeneration strategies that are not dependent on the endogenous thymus, such as transplantation of bipotent thymic epithelial cell progenitors to reconstitute thymus lobules and functions. Illustration designed with Biorender.
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References

    1. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: A Link Between Cancer Genetics and Chemotherapy. Cell (2002) 108:153–64. doi: 10.1016/S0092-8674(02)00625-6 - DOI - PubMed
    1. Malhotra V, Perry MC. Classical Chemotherapy: Mechanisms, Toxicities and the Therapeutic Window. Cancer Biol Ther (2003) 2:S2–4. doi: 10.4161/cbt.199 - DOI - PubMed
    1. Damia G, D'Incalci M. Mechanisms of Resistance to Alkylating Agents. Cytotechnology (1998) 27:165–73. doi: 10.1023/A:1008060720608 - DOI - PMC - PubMed
    1. Parker WB. Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer. Chem Rev (2009) 109:2880–93. doi: 10.1021/cr900028p - DOI - PMC - PubMed
    1. Rowinsky EK, Donehower RC. The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics. Pharmacol Ther (1991) 52:35–84. doi: 10.1016/0163-7258(91)90086-2 - DOI - PubMed

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