TNF in the era of immune checkpoint inhibitors: friend or foe?

Abstract

Immune checkpoint inhibitors (ICIs) are effective in the treatment of patients with advanced cancer and have emerged as a pillar of standard cancer care. However, their use is complicated by adverse effects known as immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis. ICI-induced inflammatory arthritis is distinguished from other irAEs by its persistence and requirement for long-term treatment. TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis, spondyloarthropathies and inflammatory bowel disease, and have also been adopted as second-line agents to treat irAEs refractory to glucocorticoid treatment. Experiencing an irAE is associated with a better antitumour response after ICI treatment. However, whether TNF inhibition can be safely used to treat irAEs without promoting cancer progression, either by compromising ICI therapy efficacy or via another route, remains an open question. In this Review, we discuss clinical and preclinical studies that address the relationship between TNF, TNF inhibition and cancer. The bulk of the evidence suggests that at least short courses of TNF inhibitors are safe for the treatment of irAEs in patients with cancer undergoing ICI therapy. Data from preclinical studies hint that TNF inhibition might augment the antitumour effect of ICI therapy while simultaneously ameliorating irAEs.

Figure 1:. Pro-tumour and anti-tumour effects of TNF inhibition and ICI therapy.

A model of immune interactions in the tumour microenvironment. CTLs have direct cytotoxic effects on cancer cells, and moreover serve as a hub to integrate the indirect effects of other immune cell types, TNF inhibition and ICI therapy. Naïve CD8⁺ T cell differentiation replenishes the CTL pool. NK cells, T_H1 cells, and tumour-associated macrophages have direct effects on cancer cell proliferation, and integrate the indirect effects of other immune cell types and TNF inhibition. TNF inhibition has a direct inhibitory effect on cancer cell proliferation. This model maps the different paths by which TNF inhibition exerts pro-tumour or anti-tumour effects. Each path starts with TNF inhibition exerting a direct effect on a cell type; *denotes that the effect of TNF inhibition is inferred from experimental data on TNF