Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice
Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice
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DOI：
10.1158/2326-6066.cir-14-0190
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发表时间：
2015-06-01
影响因子：
10.1
通讯作者：
Matsushima, Kouji
中科院分区：
文献类型：
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作者：
Ueha, Satoshi;Yokochi, Shoji;Matsushima, Kouji
CD4（+）细胞在荷瘤小鼠体内的消耗具有很强的抗肿瘤作用。然而，这些作用的机制以及CD4（+）细胞消耗相对于其他免疫疗法的治疗益处尚未得到充分评估。在这里，我们研究了抗cd4消耗单抗作为单一疗法或与免疫检查点单抗联合的抗肿瘤作用。在B16F10、Colon 26或Lewis肺癌皮下肿瘤模型中，单独给药抗cd4单抗具有较强的抗肿瘤作用，优于CD25(+) Treg缺失或其他免疫检查点单抗，并且被CD8（+）细胞缺失完全逆转。CD4（+）细胞耗竭导致引流淋巴结中肿瘤特异性CD8(+) T细胞增殖，PD-1(+)CD8(-) T细胞进入肿瘤的浸润增加，肿瘤内向I型免疫转变。抗cd4单抗和免疫检查点单抗联合治疗，特别是抗pd -1或抗pd - l1单抗，协同抑制肿瘤生长并大大延长生存期。据我们所知，这项研究首次报道了抗cd4和抗pd -1或抗pd - l1单抗疗法之间的强大协同作用。AACR (C) 2015。
Depletion of CD4(+) cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4(+) cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25(+) Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8(+) cell depletion. CD4(+) cell depletion led to the proliferation of tumor-specific CD8(+) T cells in the draining lymph node and increased infiltration of PD-1(+)CD8(-) T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies. (C)2015 AACR.