Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-β in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.

中文翻译：

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IL-7/αIL-7 mAb M25 免疫复合物扩增 CD8+ T 细胞，但矛盾的是取消了 CTLA-4 和 PD-1 阻断的抗肿瘤活性

IL-7 的超生理水平诱导前 B 细胞、幼稚 T 细胞和记忆表型 CD8+ T 细胞的数量增加。IL-7 和 αIL-7 mAb M25 (IL-7/M25) 的免疫复合物在体内被描述为 IL-7 超激动剂。因此，用 IL-7/M25 处理小鼠显着增加了 T 细胞库的大小。我们决定在荷瘤小鼠中使用 αCTLA-4 和 αPD-1 mAb 之前，使用 IL-7/M25 来扩大 T 细胞群，进而促进基于 CTLA-4 和PD-1 阻塞。我们发现，仅四剂 IL-7/M25 就使脾细胞的绝对数量增加了大约五倍，并显着改变了 CD4+：CD8+ T 细胞比例，有利于 CD8+ T 细胞。CD8+ T 细胞内记忆表型 CD8+ T 细胞的相对计数也显着增加（约三倍），但 CD4+ T 细胞内 Treg 细胞的相对计数显着减少（约 30%）。所有这些数据表明 IL-7/M25 提供了一种合适的方法来通过 CTLA-4 和 PD-1 阻断来增强肿瘤免疫治疗。出乎意料的是，IL-7/M25 在以下小鼠肿瘤模型中显着消除了 αCTLA-4 和 αPD-1 mAb 的抗肿瘤活性：MC-38 和 CT26 结肠癌和 B16F10 黑色素瘤。IL-7/M25 对 CTLA-4 和 PD-1 阻断的抗肿瘤活性的这种自相矛盾的作用不是通过血清中 IL-10 或 TGF-β 水平的增加或产生 IL-10 的 B 细胞计数增加介导的或注射了 IL-7/M25 的小鼠脾脏中的 T 细胞。因此，