Pulmonary toxicity of immune checkpoint immunotherapy

Abstract

Cancer remains a leading cause of mortality on a global scale. Lung cancer, specifically non-small cell lung cancer (NSCLC), is a prominent contributor to this burden. The management of NSCLC has advanced substantially in recent years, with immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), leading to improved patient outcomes. Although generally well tolerated, the administration of ICIs can result in unique side effects known as immune-related adverse events (irAEs). The occurrence of irAEs involving the lungs, specifically checkpoint inhibitor pneumonitis (CIP), can have a profound effect on both future therapy options and overall survival. Despite CIP being one of the more common serious irAEs, limited treatment options are currently available, in part due to a lack of understanding of the underlying mechanisms involved in its development. In this Review, we aim to provide an overview of the epidemiology and clinical characteristics of CIP, followed by an examination of the emerging literature on the pathobiology of this condition.

Figure 1. Immune checkpoint biology.

(A) T cell activation is initiated by interacting via its T cell receptor with APCs that present offending antigens. A costimulatory signal is additionally required on the T cell CD28 receptor for full activation. Upon activation, CTLA-4 and PD-1 are expressed on the cell surface. (B) CD28 costimulation can be inhibited by CTLA-4, leading to T cell dysfunction. CTLA-4 expression can be enhanced by the tumor microenvironment (TME). Both of these steps occur at the level of the lymphoid organs. (C) Stimulation of the PD-1 receptor by tumor-expressed PD-L1 can render activated T cells dormant, inhibiting immune responses against cancer cells. These mechanisms can be overcome with specific antibodies against the receptors (CTLA-4, PD-1) or ligands (PD-L1).

Figure 2. Pathophysiological mechanisms in CIP.

The use of ICI liberates T cells from cancer-induced immunosuppression. This also triggers a number of pathways that include B and plasma cell proliferation and subsequent autoimmune antibody production (e.g., anti-CD74); release of cytokines (e.g., IL-1β, TNF-α, CXCL-10) that are involved in inflammation and can affect multiple cell types and expansion of T cells (e.g., Tcm, Th, clonal T cells) that are likely influenced by the tumor microenvironment (TME), tumor mutational burden, and self-antigens in the lung parenchyma. These different pathways converge individually or in combination to cause inflammatory damage in the lung leading to CIP. The involvement of myeloid cells in CIP is evident although not well defined. They either may act as an additional stimulus for T cell activation and expansion or are regulated by the T cell and cytokine milieu, contributing to pulmonary injury. Solid lines indicate known mechanisms involved in CIP; dashed lines indicate proposed mechanisms.