Abstract 2897: Cancer associated fibroblasts targeted photoimmunotherapy improves drug delivery
Authors: Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Tatsuya Takahashi, Yasushige Takeda, Hijiri Matsumoto, Tomoyoshi Kunitomo, Kento Kawasaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2024)

Abstract Introduction: Desmoplasia is often associated with adverse outcomes in cancer, particularly in esophageal cancers characterized by stroma-rich environments and poor prognoses. The dense extracellular matrix (ECM) within the stroma hinders effective drug delivery, primarily due to elevated interstitial pressure. Cancer-associated fibroblasts (CAFs) of the tumor microenvironment deteriorate this issue by promoting cancer proliferation and ECM production. We have developed a photoimmunotherapy targeting these CAFs via fibroblast activation protein (FAP-PIT), which has demonstrated notable antitumor efficacy in CAF-rich tumors that are typically chemoresistant. This study explores the potential of FAP-PIT to enhance drug delivery in CAF-rich tumors. Methods: We have conjugated Sibrotuzumab, a clinically-trialed FAP antibody with the photosensitizer IR700DX for application in FAP-PIT. We compared the protein expression levels of ECM components—collagen I (Col I) and hyaluronic acid (HA)—between CAFs and normal fibroblasts (NFs) in vitro. Spheroid models, both CAF-poor (solely cancer cells) and CAF-rich (cancer cells plus fibroblasts), were employed to assess drug uptake. Additionally, 140 esophageal cancer cases from 2008 to 2010 were retrospectively analyzed. In vivo, we induced bilateral subcutaneous tumors to apply FAP-PIT, monitoring drug uptake using in vivo imaging systems (IVIS) and immunohistochemistry (IHC). Results: Initially, we determined how significantly CAFs impede the drug delivery. In vitro, CAFs secreted higher levels of Col I and HA compared to NFs. Clinically, the expression of Col I and HA consistently showed a positive correlation with α-smooth muscle actin (αSMA) and FAP. CAF-rich spheroids exhibited significantly reduced uptake of fluorescently labeled chemotherapy compared to CAF-poor spheroids. Conversely, FAP-PIT enhanced drug penetration in CAF-rich spheroids through CAFs depletion and ECM remodeling. In vivo studies further demonstrated that FAP-PIT significantly increased Panitumumab and nab-Paclitaxel accumulation in CAF-rich tumors, leading to superior antitumor efficacy. IHC analysis validated the significant reduction of CAFs and Col I. Conclusion: The ECM, including CAFs, poses a barrier to drug delivery. Our findings indicate that FAP-PIT can effectively enhance drug penetration in CAF-rich tumors, presenting a novel therapeutic strategy to overcome drug resistance. Citation Format: Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Tatsuya Takahashi, Yasushige Takeda, Hijiri Matsumoto, Tomoyoshi Kunitomo, Kento Kawasaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara. Cancer associated fibroblasts targeted photoimmunotherapy improves drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2897.