Evaluating near-infrared photoimmunotherapy for targeting fibroblast activation protein-α expressing cells in vitro and in vivo,Cancer Science

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Evaluating near-infrared photoimmunotherapy for targeting fibroblast activation protein-α expressing cells in vitro and in vivo
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-28 , DOI: 10.1111/cas.15601
Jiefu Jin ₁ , James D Barnett ₁ , Balaji Krishnamachary ₁ , Yelena Mironchik ₁ , Catherine K Luo ₁ , Hisataka Kobayashi ₂ , Zaver M Bhujwalla _{1,

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Affiliation

Photoimmunotherapy (PIT), carried out using an Ab conjugated to the near infrared dye IRDye700DX, is achieving significant success in target-specific elimination of cells. Fibroblast activation protein alpha (FAP-α) is an important target in cancer because of its expression by cancer-associated fibroblasts (CAFs) as well as by some cancer cells. Cancer-associated fibroblasts that express FAP-α have protumorigenic and immune suppressive functions. Using immunohistochemistry of human breast cancer tissue microarrays, we identified an increase of FAP-α⁺ CAFs in invasive breast cancer tissue compared to adjacent normal tissue. We found FAP-α expression increased in fibroblasts cocultured with cancer cells. In proof-of-principle studies, we engineered human FAP-α overexpressing MDA-MB-231 and HT-1080 cancer cells and murine FAP-α overexpressing NIH-3T3 fibroblasts to evaluate several anti-FAP-α Abs and selected AF3715 based on its high binding affinity with both human and mouse FAP-α. After conjugation of AF3715 with the phthalocyanine dye IR700, the resultant Ab conjugate, FAP-α-IR700, was evaluated in cells and tumors for its specificity and effectiveness in eliminating FAP-α expressing cell populations with PIT. Fibroblast activation protein-α-IR700-PIT resulted in effective FAP-α-specific cell killing in the engineered cancer cells and in two patient-derived CAFs in a dose-dependent manner. Following an intravenous injection, FAP-α-IR700 retention was three-fold higher than IgG-IR700 in FAP-α overexpressing tumors, and two-fold higher compared to WT tumors. Fibroblast activation protein-α-IR700-PIT resulted in significant growth inhibition of tumors derived from FAP-α overexpressing human cancer cells. A reduction of endogenous FAP-α⁺ murine CAFs was identified at 7 days after FAP-α-IR700-PIT. Fibroblast activation protein-α-targeted near infrared PIT presents a promising strategy to eliminate FAP-α⁺ CAFs.

中文翻译：

评估近红外光免疫疗法在体外和体内靶向成纤维细胞活化蛋白-α表达细胞的效果

光免疫疗法 (PIT) 使用与近红外染料 IRDye700DX 结合的 Ab 进行，在靶向特异性细胞消除方面取得了重大成功。成纤维细胞活化蛋白 α (FAP-α) 是癌症的重要靶标，因为它在癌症相关成纤维细胞 (CAF) 和一些癌细胞中表达。表达 FAP-α 的癌症相关成纤维细胞具有致癌和免疫抑制功能。使用人乳腺癌组织微阵列的免疫组织化学，我们发现 FAP-α ⁺ 与邻近的正常组织相比，浸润性乳腺癌组织中的 CAF。我们发现在与癌细胞共培养的成纤维细胞中 FAP-α 表达增加。在原理验证研究中，我们设计了人 FAP-α 过表达 MDA-MB-231 和 HT-1080 癌细胞和小鼠 FAP-α 过表达 NIH-3T3 成纤维细胞，以评估几种抗 FAP-α 抗体，并根据其与人和小鼠 FAP-α 的高结合亲和力。在 AF3715 与酞菁染料 IR700 缀合后，生成的 Ab 缀合物 FAP-α-IR700 在细胞和肿瘤中评估了其在用 PIT 消除表达 FAP-α 的细胞群中的特异性和有效性。成纤维细胞活化蛋白-α-IR700-PIT 以剂量依赖的方式在工程癌细胞和两种患者来源的 CAF 中导致有效的 FAP-α 特异性细胞杀伤。静脉注射后，FAP-α-IR700 在 FAP-α 过表达肿瘤中的保留比 IgG-IR700 高三倍，与 WT 肿瘤相比高两倍。成纤维细胞活化蛋白-α-IR700-PIT 导致源自 FAP-α 过表达人类癌细胞的肿瘤的显着生长抑制。减少内源性 FAP-α⁺ 小鼠 CAF 在 FAP-α-IR700-PIT 后 7 天被鉴定。成纤维细胞活化蛋白-α-靶向近红外 PIT 提出了消除 FAP-α ⁺ CAF 的有前途的策略。

更新日期：2022-09-28

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