Fibroblast activation protein-targeted near-infrared photoimmunotherapy depletes immunosuppressive cancer-associated fibroblasts and remodels local tumor immunity

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2024年3月30日

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Masaaki Akai,
Kazuhiro Noma,
Takuya Kato,
Seitaro Nishimura,
Hijiri Matsumoto,
Kento Kawasaki,
Tomoyoshi Kunitomo,
Teruki Kobayashi,
Noriyuki Nishiwaki,
Hajime Kashima,
Satoru Kikuchi,
Toshiaki Ohara,
Hiroshi Tazawa,
Peter L. Choyke,
Hisataka Kobayashi,
Toshiyoshi Fujiwara

摘要

Background

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage.

Methods

In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP⁺ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity.

Results

FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8⁺ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8⁺ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity.

Conclusions

Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF⁺ tumors.