Immune Checkpoint Inhibitor-Associated Cutaneous Adverse Events: Mechanisms of Occurrence

Abstract

Immunotherapy, particularly that based on blocking checkpoint proteins in many tumors, including melanoma, Merkel cell carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast (TNB cancer), renal cancer, and gastrointestinal and endometrial neoplasms, is a therapeutic alternative to chemotherapy. Immune checkpoint inhibitor (ICI)-based therapies have the potential to target different pathways leading to the destruction of cancer cells. Although ICIs are an effective treatment strategy for patients with highly immune-infiltrated cancers, the development of different adverse effects including cutaneous adverse effects during and after the treatment with ICIs is common. ICI-associated cutaneous adverse effects include mostly inflammatory and bullous dermatoses, as well as severe cutaneous side reactions such as rash or inflammatory dermatitis encompassing erythema multiforme; lichenoid, eczematous, psoriasiform, and morbilliform lesions; and palmoplantar erythrodysesthesia. The development of immunotherapy-related adverse effects is a consequence of ICIs' unique molecular action that is mainly mediated by the activation of cytotoxic CD4⁺/CD8⁺ T cells. ICI-associated cutaneous disorders are the most prevalent effects induced in response to anti-programmed cell death 1 (PD-1), anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and anti-programmed cell death ligand 1 (PD-L1) agents. Herein, we will elucidate the mechanisms regulating the occurrence of cutaneous adverse effects following treatment with ICIs.

Keywords: CAR T cells; CTLA-4; ICIs; PD-1.

Figure 1

Proposed models of CTLA-4- and PD-1-mediated regulation of T cells. (A) CTLA-4-mediated T-cell activation. Naive T-cell activation is mediated by both TCR and CD28 signaling. CTLA-4 expression results in the inhibition of activated T cells by directly competing with CD28 for ligand binding and/or by generating inhibitory signals. Whereas suboptimal co-stimulation of T cells and CTLA-4 expression leads to direct competition between CD28 and CTLA-4 for ligand binding, optimal co-stimulation is essential for limiting full T-cell activation. The successful competition of CTLA-4 against CD28 mediates inhibitory signals, which terminate the T-cell response. (B) Programmed Death (PD)-1-mediated regulation of T cells. The recognition of the MHC–antigen complex by the T-cell receptor (TCR) and CD4 leads to LCK kinase-mediated phosphorylation of the CD3-TCRζ complex. PD-1 ligation by its ligands brings PD-1 close to TCR, allowing the SHP-2 phosphatase to dephosphorylate the CD3-TCRζ complex and attenuate the signal.

Figure 2

CTLA-4-mediated inhibition of T cells. T cells are activated when TCRs bind antigens, which are presented by MHC on APCs, and by CTLA-4:B7- and CD28:B7-mediated stimulation. (A) The weak T-cell activation-dependent TCR stimulus is mediated by CD28:B7 binding, leading to the transduction of positive T-cell-intrinsic signaling, and by CTLA-4:B7 binding, leading to the transduction of negative T-cell-intrinsic signaling. MHC: TCR binding leads to the transduction of weak T-cell-intrinsic signaling. All transduced signals result in the generation of a net positive signal, which leads to IL-2 production and enhanced proliferation and survival of T cells. (B) T-cell activation-dependent strong TCR stimulus. CTLA-4 expression is upregulated by increased transport from intracellular stores to the cell surface and reduced internalization. CTLA-4 competes with CD28 for binding of B7 molecules. Increased CTLA-4:B7 binding may result in a net negative signal that limits IL-2 production and proliferation while restricting T-cell survival. CTLA-4 indicates cytotoxic T-lymphocyte-associated antigen 4; IL-2: interleukin-2; MHC: major histocompatibility complex; TCR: T-cell receptor. Red arrow: means negative signal; while green arrow: means weak or positive siganal.

Figure 2

CTLA-4-mediated inhibition of T cells. T cells are activated when TCRs bind antigens, which are presented by MHC on APCs, and by CTLA-4:B7- and CD28:B7-mediated stimulation. (A) The weak T-cell activation-dependent TCR stimulus is mediated by CD28:B7 binding, leading to the transduction of positive T-cell-intrinsic signaling, and by CTLA-4:B7 binding, leading to the transduction of negative T-cell-intrinsic signaling. MHC: TCR binding leads to the transduction of weak T-cell-intrinsic signaling. All transduced signals result in the generation of a net positive signal, which leads to IL-2 production and enhanced proliferation and survival of T cells. (B) T-cell activation-dependent strong TCR stimulus. CTLA-4 expression is upregulated by increased transport from intracellular stores to the cell surface and reduced internalization. CTLA-4 competes with CD28 for binding of B7 molecules. Increased CTLA-4:B7 binding may result in a net negative signal that limits IL-2 production and proliferation while restricting T-cell survival. CTLA-4 indicates cytotoxic T-lymphocyte-associated antigen 4; IL-2: interleukin-2; MHC: major histocompatibility complex; TCR: T-cell receptor. Red arrow: means negative signal; while green arrow: means weak or positive siganal.

Figure 3

Mechanisms of CTLA-4 and PD-1 signaling-mediated T-cell inhibition. CTLA-4 and PD-1 negatively regulate T-cell activation. CD28 mediates TCR and MHC attachment. CTLA-4 acts as a competitive homolog to CD28 and binds to CD80/CD86, ligands of CD28, thereby preventing T-cell activation. Both the CTLA-4 and PD-1 pathways are activated via TCR-dependent activation. CD28 receptor is a relevant target of PD-1-mediated inhibition. PD-1 binding to PD-L1 also negatively regulates T-cell activation through the recruitment of SHP-CTLA-4, and PD-1 recruited SHP-2 inhibits PI3K downstream signaling. CTLA-4 reacts with PP2A to dephosphorylate AKT, leading to inhibition of T-cell activation. PD-1:PD-L1 binding inhibits TCR-mediated positive signaling, leading to reduced proliferation of T cells. SHP-2: Src homology region-2 containing protein tyrosine phosphatase; PP2A: serine/threonine phosphatase PP2A.

Figure 4

The role of CTLA-4 in regulating T-cell activation and Treg-cell function. (A) CTLA-4 interacts with CD80/86 on APCs to compete with CD28 for ligands. CTLA-4 is characterized by a higher binding affinity for CD80/86 than those of CD28 and thereby CTLA-4 can block the interaction of CD80/CD86 with CD28. (B) CTLA-4 on Treg cells binds to CD80/86 on APCs, blocks costimulatory signaling in conventional T cells, and depletes CD80/86 by trans-endocytosis. Therefore, CD28 of conventional T cells cannot interact with CD80/86, which may lead to a reduction in T-cell activation. The ability of CTLA-4 to induce indolamine 2, 3-dioxygenase (IDO) from antigen presenting cells (APCs) is a mechanism whereby the CTLA-4 triggers T-cell inhibition.

Figure 5

Mechanisms of PD-1/PD-L1 pathway-dependent tumor immune escape. (A) Binding of PD-1 to PD-L1 on the surface of immune effector cells (T cells) suppresses T cell receptors (TCR) in recognizing the major histocompatibility (MHC) molecules on the surface of antigen presenting cells (APCs)/tumor cells. (B) The inhibition of PD1 binding to PD-L1 by either anti-PD-1 or PD-L1 antibodies enhances the activation of T cells through binding of TCR to MHC on the surface of APCs to trigger tumor cell death.

Figure 6

Immune checkpoint inhibitors: anti-CTLA-4 antibodies (CTLA-4 mAbs), anti-PD1 antibodies (PD-1 mAbs) block CTLA-4 and PD-1 receptors on the surface of T cells. ICI-induced accumulation of activated CD8⁺ T-cell population is characterized by T-cell receptors (TCR) and chemokine receptors (CXCR) expression and the production of perforin, granzymes, and cytokines such as interferon gamma (IFNγ), interleukin (IL)-4, IL-9, IL-13, IL-17, and IL-22. ICI-induced accumulation of activated CD4⁺ T cells is characterized by the production of pro-inflammatory cytokines including IL-17, IL-22, CXCL10, and TNF. ICI-induced activation of B cells is associated with the production of autoantibodies associated with bolus pemphigoid and autoantibody-mediated cell damage. Mechanisms of ICI-induced vitiligo: The activation of CD8⁺ T-cell populations by ICIs results in a release of IFNγ that can enhance keratinocyte activation to produce the chemokines CXC9 and CXC10, which ultimately recruit CD8⁺ T cells to the epidermis to enhance melanocyte loss and allow vitiligo development. Mechanisms of ICI-induced pruritus: The production of IL-13 by CD8⁺ T cells enhances keratinocyte activation which increases the expression of itch-associated receptors and pruritus development. Mechanisms of ICI-induced atopic eczema, psoriasiform lesions, lichenoid, and morbilliform are mediated by the pro-inflammatory cytokines IL-17, IL-22, CXCL10, and TNF released by ICI-induced CD4+ T-cell activation. Mechanisms of ICI-induced bullous pemphigoid: The blockade of PD-1/PDL-1 by ICIs in T cells enhances B-cell activation, leading to the production of disease-specific autoantibodies. These autoantibodies include IgG and IgE, which induce subepidermal blistering via direct and indirect mechanisms. The cross-reactive immunogenicity of IgG4 against the basement membrane proteins BP180 and BP230 leads to the direct formation of subepidermal blistering. IgE induces the formation of subepidermal blistering via the enhancement of mast cell degranulation and the recruitment of eosinophiles and neutrophiles, which release proteolytic enzymes. IgG1 also induces subepidermal blistering via complement activation-mediated mast cell degranulation to recruit eosinophiles and neutrophiles.