Cancer Res：缓解免疫功能紊乱促进老年鼠肿瘤免疫疗效

老年人比年轻人更可能患癌症，老年人的身体往往往往不能不足以打肿瘤这一战，接受治疗产生的毒副作用也较多。

但圣安东尼奥得克萨斯大学健康科学中心大学癌症治疗和研究中心的研究表明：以前认为某些只有在年轻患者体内发挥作用的免疫类型也可以用来帮助老年肿瘤患者。

医药卫生科学中心公共卫生硕士Tyler Curiel医学博士、教授说：我们已经证明，免疫治疗不仅对老年癌症小鼠有效，实际上免疫治疗可能对老年癌症患者也有效。相关研究论文发表在4月15日的Cancer Research杂志上。

随着年龄的增长，人体的免疫系统会减弱，但它也发生了某些变化，包括改变身体内与疾病作斗争的规则。Curiel博士的研究小组抑制了关闭了促进癌症发展的免疫反应中的调节性T细胞。调节性T细胞在癌症的增加在年轻机体中，抑制调节性T细胞活性的药物使免疫系统能发挥更好的作用。在老年机体中，即使药物抑制了调节性T细胞，该药物也不会有临床效益。

在年纪较大的老鼠中，当药物抑制调节性T细胞后，研究人员发现另一种类型的免疫抑制细胞（髓系衍生抑制细胞MDSC）顶替了调节性T细胞的地位，阻碍了临床疗效。但上述现象这并不发生在年轻小鼠中。团队添加了针对MDSC的第二个药物后，发现老年患者可以像年轻癌症患者那样对抗癌症。

在黑色素瘤细胞研究中发现这些结果后，研究人员考察了结肠癌中是否也存在同样情况。Curiel博士说：下一步是开展老年癌症患者免疫治疗临床试验，以验证这些研究结果。

doi:10.1158/0008-5472.CAN-11-3019
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Mitigating Age-Related Immune Dysfunction Heightens the Efficacy of Tumor Immunotherapy in Aged Mice

Vincent Hurez, Benjamin J. Daniel, Lishi Sun, Ai-Jie Liu, Sara M. Ludwig, Mark J. Kious, Suzanne R. Thibodeaux, Srilakshmi Pandeswara, Kruthi Murthy, et al.

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+CD25hi 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.