Abstract 592: Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade
Abstract 592: Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade
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摘要 592：不同的细胞机制介导抗 CTLA-4 和抗 PD-1 检查点阻断
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发表时间：
2017
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通讯作者：
J. Allison
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作者：
S. Wei;Jacob H. Levine;D. Pe’er;J. Allison
检查点阻断能够在一部分患者中实现持久的缓解，然而，区分缓解者和非缓解者的生物学变量尚未得到很好的理解。此外，我们缺乏对抗CTLA-4和抗PD-1诱导的肿瘤排斥反应的潜在机制的满意理解。鉴于PD-1和CTLA-4通过空间和时间上分离的不同机制减弱T细胞活性，我们假设对抗CTLA-4和抗PD-1的应答由不同机制驱动。为了解决这一假设，我们利用质谱细胞术来全面分析检查点阻断对小鼠肿瘤模型中肿瘤免疫浸润的影响。该方法允许以单细胞分辨率询问大于40种分析物。我们证明，高维质谱细胞计数分析能够以高灵敏度和特异性无监督地鉴定生物学相关的肿瘤浸润免疫群体。使用这种方法，我们分析了用抗CTLA-4、抗PD-1或对照抗体处理的小鼠中MC 38和B16 BL 6鼠肿瘤的免疫浸润。在两种肿瘤模型中，我们鉴定出15种不同的T细胞群，频率为0.5%或更高。在MC 38和B16 BL 6肿瘤中鉴定的T细胞群是高度一致的。值得注意的是，这些T细胞群中的一些但不是全部对检查点阻断有反应。肿瘤浸润性CD 8 T细胞群的亚群在抗CTLA-4和抗PD-1后扩增。相反，调节性T细胞群的子集在抗CTLA-4和抗PD-1后收缩。有趣的是，我们观察到Th 1样CD 4效应T细胞群仅响应于抗CTLA-4治疗而扩增。因此，我们发现抗PD-1主要接合肿瘤浸润性CD 8 T细胞的亚群，而抗CTLA-4接合CD 4和CD 8效应区室两者。我们的研究结果表明，抗CTLA-4和抗PD-1利用不同的细胞机制来诱导肿瘤排斥反应。这些发现强调了扩大我们对免疫学方法的机械理解对于合理设计组合治疗方法的重要性。此外，这些结果表明，质谱细胞术分析可用于鉴定生物学相关的肿瘤浸润T细胞群。我们承认MDACC核心设施NCI支持赠款P30 CA 16672。引文格式：Spencer C.作者：Jacob H.放大图片作者：James P.不同的细胞机制介导抗CTLA-4和抗PD-1检查点阻断[摘要]。In：Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5;华盛顿，DC. Philadelphia（PA）：AACR; Cancer Res 2017;77（13 Suppl）：Abstract nr 592. doi：10.1158/1538-7445.AM2017-592
Checkpoint blockade is able to achieve durable responses in a subset of patients, however the biological variables that distinguish responders from non-responders are not well understood. Furthermore, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. Given that PD-1 and CTLA-4 attenuate T cell activity through distinct mechanisms that are separated spatially and temporally, we hypothesized that responses to anti-CTLA-4 and anti-PD-1 are driven by distinct mechanisms. To address this hypothesis we utilized mass cytometry to comprehensively profile the effect of checkpoint blockade on tumor immune infiltrates in murine tumor models. This approach allows for the interrogation of greater than 40 analytes at single cell resolution. We demonstrate that high dimensional mass cytometry analysis enables unsupervised identification of biologically relevant tumor infiltrating immune populations with high sensitivity and specificity. Using this approach we analyzed immune infiltrates of MC38 and B16BL6 murine tumors in mice treated with anti-CTLA-4, anti-PD-1, or control antibodies. In both tumor models we identify 15 distinct T cell populations with 0.5% or greater frequency. The T cell populations identified in MC38 and B16BL6 tumors were highly congruent. Notably, some but not all of these T cell populations were responsive to checkpoint blockade. A subset of tumor infiltrating CD8 T cell populations expanded following both anti-CTLA-4 and anti-PD-1. Conversely, a subset of regulatory T cell populations contracted following both anti-CTLA-4 and anti-PD-1. Interestingly, we observed expansion of a Th1-like CD4 effector T cell population only in response to anti-CTLA-4 treatment. Thus, we find that anti-PD-1 predominantly engages subsets of tumor infiltrating CD8 T cells whereas anti-CTLA-4 engages both the CD4 and CD8 effector compartments. Our findings indicate that anti-CTLA-4 and anti-PD-1 utilize distinct cellular mechanisms to induce tumor rejection. These findings highlight the importance of expanding our mechanistic understanding of immunotherapeutic approaches for the rational design of combinatorial therapeutic approaches. Furthermore, these results demonstrate that mass cytometry analysis can be utilized to identify biologically relevant tumor infiltrating T cell populations. We acknowledge the MDACC core facility NCI Support Grant P30CA16672. Citation Format: Spencer C. Wei, Jacob H. Levine, Dana Pe9er, James P. Allison. Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2017-592