Treatment of Pancreatic Cancer Using Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Combination with Anticancer Chemotherapeutic Drug

TL;DR

A new treatment combining light therapy and chemotherapy shows promise in fighting pancreatic cancer by targeting supportive cells in the tumor.

Contribution

This study introduces a novel approach using NIR-PIT to target CAFs in PDAC, enhancing chemotherapy effectiveness.

Findings

NIR-PIT targeting CAFs reduced pancreatic cancer cell proliferation in co-culture experiments.

Combining NIR-PIT with gemcitabine significantly reduced tumor volume in mice compared to gemcitabine alone.

NIR-PIT alone did not reduce tumor volume compared to controls.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to its dense stroma rich in cancer-associated fibroblasts (CAFs), which promote tumor progression and treatment resistance. This study evaluated near-infrared photoimmunotherapy (NIR-PIT), targeting CAFs in PDAC. An anti-fibroblast activation protein (FAP) antibody conjugated to IRDye®700DX (αFAP-IR700) was tested on pancreatic cancer cells and hPSC-5 (CAFs). αFAP-IR700 successfully bound to hPSC-5, inducing cell death by NIR-PIT. Pancreatic cancer cells exhibited enhanced proliferation when co-cultured with hPSC-5, but this effect was reduced by NIR-PIT. In vivo, combining NIR-PIT with gemcitabine (GEM) significantly reduced tumor volume compared to GEM alone. These results suggest that targeting stromal cells with NIR-PIT enhances the efficacy of chemotherapy, providing a promising therapeutic strategy for PDAC.

Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC.

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