Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration.
Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration.
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DOI：
10.1158/1078-0432.ccr-18-1038
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发表时间：
2018-11-01
期刊：
影响因子：
--
通讯作者：
Karam SD
中科院分区：
文献类型：
--
作者：
Oweida A;Hararah MK;Phan A;Binder D;Bhatia S;Lennon S;Bukkapatnam S;Van Court B;Uyanga N;Darragh L;Kim HM;Raben D;Tan AC;Heasley L;Clambey E;Nemenoff R;Karam SD
放射治疗（RT）可以改变免疫格局，使免疫原性差的肿瘤对PD-L1抑制敏感。在这里，我们确定了对RT和PD-L1联合抑制的反应是短暂的，并研究了耐药机制。使用质谱细胞术和全基因组测序研究了原位小鼠头颈部鳞状细胞癌（HNSCC）肿瘤对RT和PD-L1阻断的耐药机制。用单独的抗PD-L1或抗TIM-3以及与RT组合和不与RT组合治疗小鼠。评估肿瘤生长和存活。流式细胞术用于评估肿瘤内T细胞群的表型和功能变化。使用抗CD 25抗体进行调节性T细胞（Treg）的消耗。我们发现，免疫检查点受体TIM-3在用RT和PD-L1阻断剂治疗的肿瘤中在CD 8 T细胞和TcB上上调。在HNSCC的原位模型中，用抗TIM-3与抗PD-L1和RT同时治疗导致显著的肿瘤生长延迟、增强的T细胞细胞毒性、降低的TcR和改善的存活。尽管有这种治疗组合，但反应并不持久，对复发肿瘤的分析显示THBE的复苏。然而，靶向Treg耗竭恢复了用RT和双重免疫检查点阻断治疗的小鼠的抗肿瘤免疫力，并导致肿瘤排斥和免疫记忆的诱导。这些数据揭示了可以促进肿瘤发生的多层免疫调节以及顺序靶向克服肿瘤耐药机制的治疗潜力。我们提出靶向Treg抑制剂可能是实现联合放疗和免疫治疗的持久肿瘤反应的关键。针对程序性死亡1/程序性死亡配体1（PD-1/PD-L1）轴的免疫治疗临床试验显示，大多数头颈部鳞状细胞癌（HNSCC）患者对PD-1/PD-L1抑制剂耐药。我们的研究结果揭示了肿瘤免疫逃避机制的复杂性，并强调了调节性T细胞在HNSCCs治疗抵抗中的关键作用。
Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance. Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti–PD-L1 or anti–TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody. We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti–TIM-3 concurrently with anti–PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory. These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Immunotherapy clinical trials targeting the programmed-death 1/programmed-death ligand 1 (PD-1/PD-L1) axis show that a majority of head and neck squamous cell carcinoma (HNSCC) patients are resistant to PD-1/PD-L1 inhibition. Our findings reveal the complexity of tumor immune evasion mechanisms and underscore the critical role regulatory T cells play in treatment resistance of HNSCCs.
影响因子：
1.7
作者：
Tan, Marietta;Myers, Jeffrey N.;Agrawal, Nishant
通讯作者：
Agrawal, Nishant