Transcriptomics

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Identification of cathepsin L as an inter-organ target to mitigate cachexia while enhancing tumor suppression by anti-PD-L1


ABSTRACT: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.

ORGANISM(S): Mus musculus

PROVIDER: GSE278013 | GEO | 2024/10/01

REPOSITORIES: GEO

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