Hypothalamic expression of PD-L1: does it mediate hypothalamitis?

Recently, immune checkpoint inhibitors have revolutionized the landscape of advanced cancer treatment. The specific blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-protein 1 (PD-1) or its ligand (PD-L1) with monoclonal antibodies augments the immunological reaction against tumor cells in several cancer types. CTLA-4 belongs to the B7:CD28 immunoglobulin family. It is expressed on the surface of T-cells and is able to generate a signal that inhibits T-cells. Ipilimumab is a human monoclonal antibody that deactivates the inhibitory signal mediated by CTLA-4 to T-cells.¹ Similarly, PD-1 is expressed on T-cells and binds PD-L1 and PD-L2 expressed on other immune cells and cancer cells. Antibodies against PD-1, such as nivolumab, pembrolizumab, and pidilizumab, or PD-L1, such as durvalumab and atezolizumab, augment the anti-tumor T-cell response by blocking the interaction between PD-1 and PD-L1 to avoid T-cell inactivation.¹ Unfortunately, re-establishing immune activity with these drugs may also impair self-tolerance, eliciting an immune response against normal tissues and organs.²

The article by N. Tshuma et al.³ reported the development of a destructive inflammatory hypothalamic mass during treatment with atezolizumab.

We report the expression of the PD-L1 receptor on hypothalamic cells, which may drive autoimmune attack during this pharmacological treatment.

Experiments

We performed indirect immunofluorescence staining of several sections of primate hypothalamus (Euroimmun, Italy) with a commercially available anti-PD-L1 monoclonal antibody (clone MIH1, eBioscience), followed by staining with an Alexa Fluor Plus 488-conjugated goat anti-mouse antibody (Thermo Fisher Scientific). As depicted in Fig. 1a, b, PD-L1 appeared to be expressed on hypothalamic cells. The specificity of the reaction was confirmed by the use of an irrelevant monoclonal antibody (clone P3.6.8.1, Thermo Fisher Scientific) (Fig. 1c).

Fig. 1.

PD-L1 expression in the hypothalamus. Both panel (a) and panel (b) represent the staining observed using a monoclonal antibody against PD-L1. Panel (c) represents a staining control using an irrelevant monoclonal antibody. One representative experiment out of five experiments is shown

Discussion

The introduction of immune checkpoint blockade has enhanced survival in patients with melanoma and lung and renal cancer and will probably also help patients with other malignancies. Thus, the clinical use of immune checkpoint inhibitors is likely to grow in coming years. Unfortunately, these systemic drugs may also activate inflammatory immune reactions in organs other than the target organs, even though we know that anti-PD-1 and PD-L1 monoclonal antibodies appear to be generally less toxic than anti-CTLA-4 mAbs⁴. However, the increase in the use of immunotherapy has led or will certainly lead to an increase in the incidence of immune-related side effects in the near future. Among these effects, we can include autoimmune endocrine diseases such as thyroiditis and hypophysitis² as well as the newly described disease hypothalamitis.³

This brief report, showing the expression of PD-L1 on hypothalamic cells, confirms the message of the study by N. Tshuma et al.³ and highlights the need for vigilance for unexpected immune-related side effects, which could have a serious impact on long-term patient health. In fact, as patients live longer and cures for advanced malignancies are developed, a new set of concerns may need to be managed.

Finally, our study suggests a mechanism to explain the hypothalamic toxicity observed in a patient receiving atezolizumab and provides tools to improve the understanding of the immune-related adverse events observed during cancer immunotherapy.

Competing interests

The authors declare no competing interests.