Department of Medicine, University of Texas Health Science Center at San Antonio, Adult Cancer Program STRF MC8252, San Antonio, Texas 78229, USA.
Cancer Res. 2012 Apr 15;72(8):2089-99. doi: 10.1158/0008-5472.CAN-11-3019. Epub 2012 Apr 11.
Although cancer tends to affect the elderly, most preclinical studies are carried out in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific tumor-associated immune dysfunction. Both young and aged CD4(+)CD25(hi) regulatory T cells (Treg) exhibited equivalent in vitro T-cell suppression and tumor-associated augmentation in numbers. However, denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSCs in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr-1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat tumor when underlying tumor-associated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for age-related tumor-associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved.
虽然癌症往往会影响老年人，但大多数临床前研究都是在年轻受试者中进行的。在这项研究中，我们开发了一种针对黑色素瘤的癌症免疫疗法，通过减轻与年龄相关的肿瘤相关免疫功能障碍，在老年宿主中显示出疗效，但在年轻宿主中没有疗效。年轻和老年的 CD4(+)CD25(hi)调节性 T 细胞（Treg）在体外均表现出等效的 T 细胞抑制作用和肿瘤相关的数量增加。然而，白细胞介素二氢睾酮（DT）介导的 Treg 耗竭仅在年轻小鼠中改善了肿瘤特异性免疫，并且具有临床疗效。DT 介导的 Treg 耗竭在老年小鼠中显著增加了髓源抑制细胞（MDSC）的数量，但在年轻小鼠中没有增加。MDSC 耗竭在老年小鼠中改善了肿瘤特异性免疫并减少了肿瘤生长。与单独使用抗-Gr-1 抗体相比，在老年 B16 荷瘤小鼠中，Treg 耗竭联合抗-Gr-1 抗体在免疫和临床方面都更有效，类似于在年轻小鼠中单独使用 Treg 耗竭。相反，DT 在 MC-38 肿瘤挑战后增加了年轻和老年小鼠中的 MDSC，但老年小鼠的效果更大。抗-Gr-1 增强了 DT 在年轻小鼠中的作用，但不能增强老年小鼠中的作用。因此，当适当减轻潜在的肿瘤相关免疫功能障碍时，老年抗肿瘤免疫效应细胞有能力对抗肿瘤，但这种功能障碍随肿瘤而变化，因此对免疫治疗的反应也不同。通过将免疫疗法调整为适应与年龄相关的肿瘤相关免疫功能障碍，可以显著改善特定肿瘤老年患者的癌症免疫疗法。
