025 ALA-PDT inhibits skin squamous cell carcinoma (cSCC) via regulating formation of tertiary lymphoid structures

Abstract

Topical ALA-mediated PDT, ALA-PDT, is a novel therapeutic modality widely used to treat actinic keratosis, Bowen’s Disease, superficial skin SCC, and other cancerous and precancerous skin diseases. Several studies have proved that ALA-PDT can inhibit SCC growth. Subsequent research suggested that ALA-PDT not only directly induced tumor cells apoptosis, but also improve tumor microenvironment through regulation of immune cells. However, the anti-tumor immune function of ALA-PDT is still need to be elucidated. Here, we found that tertiary lymphoid structures (TLSs), which are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumors, play a pivotal role in anti-tumor immune function of ALA-PDT. We analyzed 77 samples of cSCC patient in our hospital. TLS was observed in 79% of the patient samples, and the density of TLS is negatively correlation with the Brodes classification of cSCC. Intriguingly, immunohistochemistry showed that ALA-PDT could promote the formation of TLS in vivo. We also found that promotion effect of ALA-PDT on TLS is mediated by M1 macrophage, which function as lymphoid tissue inducer cells in TLS formation and recruited by ALA-PDT. Further investigation substantiated that PDT-secreted exosomes were involved in M1 macrophage polarization. Our study elucidated a mechanism that ALA-PDT influence M1 macrophage polarization via PDT-secreted exosomes, which could facilitate the formation of TLS. Thus, our research may contribute to in-depth molecular understanding of the ALA-PDT on anti-tumor immune function.