T follicular helper cells: linking cancer immunotherapy and immune-related adverse events

Abstract

Cancer immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of numerous cancer types. As the underlying mechanism of these treatments lies in the interference with inhibitory signals that usually impair potent antitumor immunity, for example, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein 1 (PD-1):programmed death-ligand 1/2 (PD-L1/2) pathway, it is not surprising that this could also promote exaggerated adaptive immune responses to unrelated antigen specificities. One of the side effects of ICI-based cancer immunotherapy that is increasingly observed in the clinic is immune-related adverse events (irAEs), including various types of autoimmunity. However, the precise etiology is incompletely understood. T follicular helper (Tfh) cells provide essential help to B cells for potent antibody responses and their tumor tissue presence is often correlated with a better outcome in several solid tumor entities. Importantly, these CD4⁺ T cells express very high amounts of PD-1 and other co-stimulatory and inhibitory receptors. Here, we address the hypothesis that targeting CTLA-4 or PD-1 and its ligand PD-L1 critically impacts the function of Tfh cells in patients that receive these ICIs, thereby providing a link between ICI treatment and the development of secondary autoimmunity.

Keywords: CD4-Positive T-Lymphocytes; adaptive immunity; antibody formation; autoimmunity; costimulatory and Inhibitory T-Cell receptors.

Figure 1

Potential effects of immune checkpoint inhibitor (ICI) treatment on T follicular helper (Tfh) cell responses. (A) Tfh cell differentiation is initiated in the T cell zone of secondary lymphoid organs (SLOs) such as lymph nodes (LNs) by priming of naïve CD4⁺ T cells through dendritic cells (DCs). This involves presentation of antigenic peptides (eg, derived from drained tumor tissues) on major histocompatibility complex class II (MHC II) and co-stimulation through CD28, which is expressed on T cells. CTLA-4 inhibits CD28-induced proliferation and acts as a break. SLO-resident Tfh cells and tumor-resident Tfh-like cells (as indicated by the different brackets) provide critical help to B cells for antibody responses through T-cell receptor (TCR) recognition of cognate (tumor) antigens presented on MHC II. Tfh and Tfh-like cells deliver co-stimulatory (eg, CD40L) and receive co-inhibitory (eg, PD-1) signals to/from B cells and together with cytokines such as interleukin-21 (IL-21) instruct antibody diversification and affinity maturation. In the context of tumors, IL-21 may also promote the antitumor activity of cytotoxic T cells (CTLs). (B) ICI treatment acts at different stages of the Tfh cell response. Anti-CTLA-4 treatment boosts naïve CD4⁺ (and CD8⁺) T cell priming, thus resulting in highly activated and proliferating CD4⁺ T cells such as Tfh cells (as well as CTLs). Tfh and Tfh-like cells express high levels of PD-1 and blockade of this pathway during ICI treatment may unleash the antibody response, which may also result in the production of autoreactive antibodies. Besides its direct effect on CTLs, PD-1/PD-L1 blockade may also boost IL-21 provision to CTLs by Tfh and Tfh-like cells in LNs and tumor tissues, with the resulting exaggerated CTL response, potentially also driving autoimmune manifestations of immune-related adverse events (irAEs). Created with BioRender.com.