Does Immune Checkpoint Inhibition Have A Dark Side?

Tumors frequently evade the immune system at least in part via elevated cell-surface expression of PD-L1, which serves as an “invisibility cloak” for the growing malignancy. Immune checkpoint inhibitors counteract a key mechanism of immune evasion, activating patients’ T cells to recognize and attack tumors. PD-1 inhibitors in particular, including nivolumab and pembrolizumab, are becoming a commonplace approach for treating cancer — though they can lead to significant toxicity.¹

Researchers in Germany and Switzerland reported recently in Nature that PD-1 also serves as an “emergency shut-off switch” when T cells themselves become malignant.² Oncogene proteins trigger increased PD-1 expression in healthy T cells, which can short-circuit the early development of premalignant T cells.

In gene sequencing analyses of 150 patients with T cell non-Hodgkin lymphoma (T-NHL), an aggressive and difficult-to-treat malignancy, the researchers found that 30% harbored mutations that disrupt PD-1 expression.

They also confirmed that, in an engineered mouse model of in T-NHL, disrupting PD-1 expression triggered a profound proliferation of malignant T cells — raising serious questions about possible unintended consequences for patients undergoing PD-1 immune checkpoint inhibition therapy in the clinic.

But T cell populations are functionally and phenotypically heterogeneous, so the clinical implications are not entirely clear, cautioned the authors of a commentary accompanying the study.³

Another study demonstrated that PD-1 blockade activates only specific subsets of T cells, noted Aya Ludin, PhD, and Leonard Zon, MD, of the Harvard Stem Cell Institute in Cambridge, Massachusetts.

“This suggests that anti-PD-1 treatment might aggravate disease progression only if it induces proliferation of the specific T-cell subtype that yielded the cancer,” they wrote.