Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
Immunity. 2019 Feb 19;50(2):477-492.e8. doi: 10.1016/j.immuni.2019.01.006. Epub 2019 Feb 5.
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
在临床上，对检查点阻断治疗的耐药性是一个挑战。我们发现，虽然联合使用抗 CTLA-4 和抗 PD-1 治疗可以改善已建立的肿瘤的控制，但这种联合治疗在临床前模型和黑色素瘤患者中，在低肿瘤负担（LTB）状态下会损害抗肿瘤免疫。激活的肿瘤特异性 T 细胞表达更高水平的干扰素-γ（IFN-γ）受体，比幼稚 T 细胞更容易凋亡。联合治疗诱导肿瘤特异性 T 细胞的删除，并改变 T 细胞库的景观，使 T 细胞向低频克隆型分布倾斜。此外，与高肿瘤负担（HTB）状态相比，联合治疗在 LTB 状态下每细胞产生更高水平的 IFN-γ，反映出 LTB 状态下免疫状态的衰竭程度较低。因此，LTB 状态下 IFN-γ 的分泌增加导致对联合检查点阻断的免疫内在耐药机制的发展，突出了实现成功的联合免疫治疗策略的最佳免疫刺激程度的重要性。
