Ubiquitin Ligases in Cancer Immunotherapy - Balancing Antitumor and Autoimmunity

Abstract

Considerable progress has been made in understanding the contribution of E3 ubiquitin ligases to health and disease, including the pathogenesis of immunological disorders. Ubiquitin ligases exert exquisite spatial and temporal control over protein stability and function, and are thus crucial for the regulation of both innate and adaptive immunity. Given that immune responses can be both detrimental (autoimmunity) and beneficial (antitumor immunity), it is vital to understand how ubiquitin ligases maintain immunological homeostasis. Such knowledge could reveal novel mechanisms underlying immune regulation and identify new therapeutic approaches to enhance antitumor immunity and safeguard against autoimmunity.

Keywords: E3 ubiquitin ligase; antitumor immunity; autoimmunity; immune checkpoint.

Figure 1:. Mechanism of T cell tolerance and activation

A) Mechanism of central and peripheral tolerance. Binding strength of the TCR to the MHC-self-peptide complex determines T cell fate during negative selection. T cells that bind with high affinity to self-antigens presented by mTECs or DCs are eliminated by a process termed clonal deletion. T cells that bind with lower affinity differentiate/mature and are released into the periphery. Peripheral tolerance is maintained by concerted activity of Tregs, APCs and T cell intrinsic regulatory cues that regulate T cell effector function, survival (Activation induced cell death, AICD) and responsiveness (anergy). B) T cell activation and anergy. TCR engagement in the context of CD28 costimulation (Signals 1 and 2) leads to reorganization of cell surface molecules into the “immune synapse”, which is critical for recruitment of proximal signaling proteins. A cascade of signaling events is initiated to cooperatively regulate T cell adhesion/migration, growth and proliferation, survival, differentiation and effector function. Production of the effector cytokine IL-2, for example, requires concerted activity of calcineurin, Ras, and PKC-θ, which, in turn, activate the transcription factors NFAT, AP-1, and NF-κB. In contrast, under anergy-inducing conditions, a distinct, largely NFAT-dependent transcriptional program is initiated that fails to upregulate IL-2 production but increases expression of several anergy-regulating genes, including the E3 Ubiquitin ligases Cbl-b, Itch, and Grail (read). These in turn limit expression/activity of major signaling proteins to reprogram T cells into a long-lasting, hyporesponsive state termed anergy. The cytokine milieu (Signal 3) also affects signaling proteins downstream of the TCR to modulate T cell activation and differentiation. APC: antigen presenting cell; MHC: major histocompatibility complex; mTEC: medullary thymic epithelial cell; Treg: regulatory T cell; AICD: activation-induced cell death; TCR: T cell receptor; Ag: Antigen; sAg: self-Ag;

Figure 2:. E3 ubiquitin ligases regulate T cell dysfunction in cancer

E3 Ubiquitin ligases (red) can serve as T cell intrinsic checkpoints to inhibit T cell function. A) T cell activity is modulated by immunosuppressive cytokines that are present in the tumor microenvironment and E3s are crucial regulators of cytokine production. B) E3s also function in T_regs where they increase immunosuppressive cytokine production and limit T_reg suppressor function. C) In innate immune cells E3s can inhibit immune-stimulatory function and/or upregulate co-inhibitory surface receptors (e.g. PD-1, CTLA-4). D) Dyregulation of ubiquitination also affects the production immunostimulatory cytokines such as type I Interferons (IFN), an effect that is influenced by stresses commonly present in the tumor microenvironment. E) Finally, E3 ubiquitin ligase function in cancer cells contributes to generate an iummunosuppressive microenvironment. CAF: cancer associated fibroblasts; MDSC: myeloid-derived suppressor cell; APC: antigen-presenting cell; PML: promyelocytic leukemia protein; TsA: tumor-specific antigen;