Leprosy as a model to understand cancer immunosurveillance and T cell anergy

Abstract

Leprosy is a disease caused by Mycobacterium leprae that presents on a spectrum of both clinical manifestations and T cell response. On one end of this spectrum, tuberculoid leprosy is a well-controlled disease, characterized by a cell-mediated immunity and immunosurveillance. On the opposite end of the spectrum, lepromatous leprosy is characterized by M. leprae proliferation and T cell anergy. Similar to progressive tumor cells, M. leprae escapes immunosurveillance in more severe forms of leprosy. The mechanisms by which M. leprae is able to evade the host immune response involve many, including the alterations of lipid droplets, microRNA, and Schwann cells, and involve the regulation of immune regulators, such as the negative checkpoint regulators CTLA-4, programmed death 1, and V-domain Ig suppressor of T cell activation-important targets in today's cancer immunotherapies. The means by which tumor cells become able to escape immunosurveillance through negative checkpoint regulators are evidenced by the successes of treatments, such as nivolumab and ipilimumab. Many parallels can be drawn between the immune responses seen in leprosy and cancer. Therefore, the understanding of how M. leprae encourages immune escape during proliferative disease states has potential to add to our understanding of cancer immunotherapy.

Immune Checkpoints in Leprosy: Immunotherapy As a Feasible Approach to Control Disease Progression

“…Although ICP have been studied for approximately two decades, many features of their biology and signaling pathways remain unknown. ICP receptors are associated with autoimmunity, suggesting that these molecules play a critical role in immune tolerance and homeostasis ( 7 , 8 ). In chronic infections, T lymphocytes are under persistent exposure to antigens, and this stimulus is commonly associated with T exhaustion ( 20 ).…”

“…Recent work has demonstrated that Tregs play a role in M. leprae -specific Th1 unresponsiveness during lepromatous disease ( 33 ). In LL, Th2/Treg polarization seems to be important to disease progression, and multiple factors may be responsible for these events, such as antigen exposure and innate immune activation ( 7 ). Otherwise, TT patients present a cellular immune response polarized to Th1/Th17 ( 31 – 33 ).…”

“…Expression of co-inhibitory molecules, such as PD-1, TIGIT, lymphocyte-activation gene-3 (LAG-3), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), on lymphocytes and their respective ligands on the APC surface (PD-L1, CD122/155, MHC class II, and B7) induce specific T-cell anergy, leading to disseminated and progressive disease. In addition, there is higher differentiation of natural and induced types of Treg cells (nTreg/iTreg), as well as an imbalance of Th cells ( 7 ). The release of IL-10 and TGF-β from heterogeneous Treg cell subsets controls the immune response by the inhibition of effector functions, as well as induces tolerogenic phenotypes in DCs ( 8 ).…”

“…The immune response often differentiates into a Th2 profile, with abundant production of IL-4 and predominant B cell activation, which allows for evasion by the bacillus. M. leprae shows strategies to limit the host protective immune response leading to chronic infection ( 6 , 7 ). In chronic infections, T cells are exposed to persistent antigen stimulation as a gradual loss of effector functions and cytokine production as well as persistently increased expression of multiple inhibitory receptors ( 6 , 8 ).…”

“…In addition, M. leprae antigens interfere with T-cell proliferation ( 10 ) and are involved in Treg-cell expansion through HSP-60 ( 11 ). Evidence has indicated that Treg cells, besides expression of immune checkpoint molecules with inhibitory activity, such as PD-1, PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), induce specific T-cell anergy, leading to disseminated and progressive disease ( 7 , 12 , 13 ). Immune checkpoint (ICP) molecules play an important role in T-cell activation and determine the functional outcome of T cells, reducing the proliferation and secretion of inflammatory cytokines, such as IL-2, IFN-γ, and TNF-α ( 14 , 15 ).…”