Title:IR-780 Dye-based Targeting of Cancer-associated Fibroblasts Improves
Cancer Immunotherapy by Increasing Intra-tumoral T Lymphocytes
Infiltration
Volume: 24
Issue: 6
Author(s): Wei Yang, Zelin Chen, Langfan Qu, Can Zhang, Hongdan Chen, Jiancheng Zheng, Wanchao Chen, Xu Tan*Chunmeng Shi*
Affiliation:
- Institute
of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University
(Army Medical University), Chongqing, 400038, China
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Institute
of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University
(Army Medical University), Chongqing, 400038, China
Keywords:
IR-780, cancer-associated fibroblasts, tumor-infiltrating lymphocytes, extracellular matrix, anti-PD-L1, cancer immunotherapy.
Abstract:
Background: Immune-checkpoint inhibitors (ICIs) against programmed death
(PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of
patients with cancer, while the rest may exhibit low response or may develop drug resistance after
initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted
by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions
of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells.
However, there is still a lack of effective therapeutic strategies to control the extracellular matrix
by targeting CAFs.
Methods: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared
fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The
fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested
by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1
by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models.
Results: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in
the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype,
while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover,
IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral
stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating
lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy.
Conclusion: This work provides a unique strategy for the inhibition of ECM protein deposition in
the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and
further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a
potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.
