Papaevangelou Efthymia, Smolarek Dorota, Smith Richard A, Dasgupta Prokar, Galustian Christine
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, UK.
Urology Centre, Guy's Hospital, London, UK.
Immunotargets Ther. 2020 Jul 27;9:115-130. doi: 10.2147/ITT.S257443. eCollection 2020.
BACKGROUND: The prostate cancer microenvironment is highly immunosuppressive; immune cells stimulated in the periphery by systemic immunotherapies will be rendered inactive once entering this environment. Immunotherapies for prostate cancer need to break this immune tolerance. We have previously identified interleukin-15 (IL-15) as the only cytokine tested that activates and expands immune cells in the presence of prostate cancer cells. In the current study, we aimed to identify a method of boosting the efficacy of IL-15 in prostate cancer. METHODS: We engineered, by conjugation to a myristoylated peptide, a membrane-localising form of IL-15 (cyto-IL-15) and the checkpoint inhibitor antibodies cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) (cyto-abs) to enable them to bind to cell surfaces by non-specific anchoring to the phospholipid bilayer. The efficacy of these agents was investigated by intratumoral administration either alone (cyto-IL-15 or cyto-abs) or in combination (cyto-combo) in subcutaneous TRAMP-C2 prostate tumors in C57BL/6J mice and compared with their non-modified equivalents in vivo. Following the survival endpoint, histological analyses and RNA sequencing were performed on the tumors. RESULTS: Intratumoral injection of cyto-IL-15 or cyto-combo delayed tumor growth by 50% and increased median survival to 28 and 25 days, respectively, compared with vehicle (17 days), whereas non-modified IL-15 or antibodies alone had no significant effects on tumor growth or survival. Histological analysis showed that cyto-IL-15 and cyto-combo increased necrosis and infiltration of natural killer (NK) cells and CD8 T cells in the tumors compared with vehicle and non-modified agents. Overall, the efficacy of cyto-combo was not superior to that of cyto-IL-15 alone. CONCLUSION: We have demonstrated that intratumoral injection of cyto-IL-15 leads to prostate cancer growth delay, induces tumor necrosis and increases survival. Hence, cytotopic modification in combination with intratumoral injection appears to be a promising novel approach for prostate cancer immunotherapy.
背景：前列腺癌微环境具有高度免疫抑制性；全身免疫疗法在外周刺激的免疫细胞一旦进入该环境就会变得无活性。前列腺癌免疫疗法需要打破这种免疫耐受。我们之前已确定白细胞介素-15（IL-15）是所测试的唯一一种在前列腺癌细胞存在的情况下能激活并扩增免疫细胞的细胞因子。在本研究中，我们旨在确定一种提高IL-15在前列腺癌中疗效的方法。 方法：我们通过与肉豆蔻酰化肽偶联，构建了一种膜定位形式的IL-15（细胞内IL-15）以及检查点抑制剂抗体细胞毒性T淋巴细胞抗原4（CTLA-4）和程序性死亡配体1（PD-L1）（细胞内抗体），使它们能够通过非特异性锚定到磷脂双层而结合到细胞表面。通过在C57BL/6J小鼠皮下TRAMP-C2前列腺肿瘤内单独（细胞内IL-15或细胞内抗体）或联合（细胞内组合）瘤内给药来研究这些药物的疗效，并在体内将其与未修饰的等效物进行比较。在达到生存终点后，对肿瘤进行组织学分析和RNA测序。 结果：与赋形剂（17天）相比，瘤内注射细胞内IL-15或细胞内组合使肿瘤生长延迟50%，中位生存期分别延长至28天和25天，而单独使用未修饰的IL-15或抗体对肿瘤生长或生存没有显著影响。组织学分析表明，与赋形剂和未修饰的药物相比，细胞内IL-15和细胞内组合增加了肿瘤中的坏死以及自然杀伤（NK）细胞和CD8 T细胞的浸润。总体而言，细胞内组合的疗效并不优于单独使用细胞内IL-15。 结论：我们已证明瘤内注射细胞内IL-15可导致前列腺癌生长延迟，诱导肿瘤坏死并延长生存期。因此，细胞内修饰与瘤内注射相结合似乎是一种有前景的前列腺癌免疫治疗新方法。
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