Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor therapy that utilizes an antibody-photo-absorbing conjugate activated by near-infrared light. In this study, we examined the therapeutic efficacy of CAF depletion by NIR-PIT in two mouse tumor models. Using CAF-rich syngeneic lung and spontaneous mammary tumors, NIR-PIT against FAP or podoplanin was performed. Anti-FAP NIR-PIT effectively depleted FAP+CAFs, as well as FAP+myeloid cells, and suppressed tumor growth, whereas anti-podoplanin NIR-PIT was ineffective. Interferon-gamma production by CD8 T and natural killer cells was induced within hours after anti-FAP NIR-PIT. Additionally, lung metastases were reduced in the treated spontaneous mammary cancer model. Depletion of FAP+stromal as well as FAP+myeloid cells effectively suppressed tumor growth in bone marrow chimeras, suggesting that the depletion of both cell types in one treatment is an effective therapeutic approach. These findings highlight a promising therapy for selectively eliminating immunosuppressive FAP+cells within the tumor microenvironment.
癌症相关成纤维细胞（CAF）是肿瘤间质中重要的细胞组分，具有多种促肿瘤发生作用。针对成纤维细胞活化蛋白（FAP）——免疫抑制性CAF中高表达标志物——的多种靶向治疗尝试，在人类临床试验中均未能显示出抗肿瘤疗效。近红外光免疫疗法（NIR-PIT）是一种高选择性肿瘤疗法，利用近红外光激活抗体-光吸收偶联物。本研究通过两种小鼠肿瘤模型，检验了NIR-PIT清除CAF的治疗效果。在富含CAF的同源肺肿瘤和自发性乳腺肿瘤模型中，分别实施了靶向FAP或平足蛋白的NIR-PIT。抗FAP NIR-PIT能有效清除FAP+CAF及FAP+髓系细胞，并抑制肿瘤生长，而抗平足蛋白NIR-PIT则无效。抗FAP NIR-PIT处理后数小时内即可诱导CD8 T细胞和自然杀伤细胞产生干扰素-γ。此外，在治疗的自发性乳腺癌模型中肺转移灶减少。骨髓嵌合体实验表明，清除FAP+间质细胞及FAP+髓系细胞能有效抑制肿瘤生长，提示单次治疗中同时清除两类细胞是有效的治疗策略。这些发现为选择性清除肿瘤微环境中的免疫抑制性FAP+细胞提供了一种前景广阔的治疗方法。
肿瘤(癌症)患者之家