Precise Modulation of Immunometabolism to Boost Antibody Therapy in Oral Cancer

“ 摘要： 抗EGFR抗体西妥昔单抗在口腔癌患者中的临床疗效仍然不佳，一个潜在的原因是由于肿瘤微环境中的免疫抑制机制，这种抗体未能诱导有效的抗癌免疫。腺苷水平升高被认为是健康组织和肿瘤的主要免疫抑制机制，它可能通过抑制抗体诱导的先天和获得性抗肿瘤免疫而导致对西妥昔单抗的耐药性。腺苷脱氨酶(ADA)催化腺苷降解为肌苷，并能逆转腺苷的免疫抑制作用。然而，全身酶给药会导致正常组织中的自身免疫紊乱，腺苷保护宿主免受过度免疫激活。我们假设，ADA靶向输送到口腔肿瘤可以精确地克服腺苷介导的免疫抑制，从而提高西妥昔单抗治疗的有效性和安全性。我们的初步研究表明，靶向递送ADA导致ADA定位于细胞表面EGFR+口腔癌细胞，表面锚定的ADA可以耗尽细胞外腺苷。在口腔癌的原位小鼠模型中，与非靶向递送相比，靶向递送导致肿瘤ADA水平显著增加。在荷瘤的同基因小鼠中，靶向ADA传递导致肿瘤微环境重新编程为免疫原性景观，并在与放射治疗相结合时导致免疫介导的肿瘤消退。在这项提案中，我们将探索这种靶向递送方法(目标1)的免疫刺激机制，并将通过使用双靶向方法(目标2)进一步优化它。这个项目可以直接转化为一种靶向癌症免疫疗法，用于治疗口腔癌患者。通过解决缺乏癌症特异性的问题，这是开发下一代癌症治疗的主要障碍，我们将为使用精确医学进行癌症免疫治疗做出贡献。

” Abstract: The clinical benefit of anti-EGFR antibody, cetuximab, remains suboptimal among patients with oral cancer, and one underlying cause is the failure of this antibody to induce potent anticancer immunity due to immunosuppressive mechanisms within the tumor microenvironments. Elevated levels of adenosine is considered a major immunosuppressive mechanism in healthy tissues and tumors, and it may cause resistance to cetuximab by suppressing innate and adaptive antitumor immunity induced by the antibody. Adenosine deaminase (ADA) catalyzes the degradation of adenosine to inosine and is capable of reversing immunosuppressive effects of adenosine. However, systemic enzyme administration causes autoimmune disorders in normal tissues, where adenosine protects the host from excessive immune activation. We hypothesize that targeted delivery of ADA into oral tumors overcomes adenosine-mediated immunosuppression precisely in the tumors, enhancing the efficacy and safety of cetuximab therapy. Our preliminary studies have shown that targeted delivery of ADA led to localization of ADA on the cell surface EGFR+ oral cancer cells, and the surface-anchored ADA could deplete extracellular adenosine. In an orthotopic mouse model of oral cancer, the targeted delivery resulted in substantial increase in tumoral ADA level compared to non-targeted delivery. In tumor-bearing syngeneic mice, targeted ADA delivery led to reprograming of tumor microenvironments into an immunogenic landscape and resulted in immune-mediated tumor regression when combined with radiation therapy. In this proposal, we will explore immunostimulatory mechanisms of this targeted delivery approach (Aim 1) and will further optimize it by using a bi-targeting method (Aim 2). This project can be directly translated into a targeted cancer immunotherapy to treat patients with oral cancer. By addressing lack of cancer specificity, a main obstacle to the development of next-generation cancer treatments, we will contribute to the use of precision medicine for cancer immunotherapy.