Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.
Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.
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DOI：
10.1038/s41598-021-85810-5
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发表时间：
2021-03-26
影响因子：
4.6
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
Slovak RJ;Park HJ;Kamp WM;Ludwig JM;Kang I;Kim HS
检查点抑制剂已在错配修复缺陷和高微卫星不稳定性的结直肠癌中显示出临床影响。然而，大多数患者患有具有稳定微卫星的疾病，对免疫疗法的反应很差。检查点抑制剂的组合正在研究中，作为增加免疫原性和促进强大的抗肿瘤免疫应答的一种方式。本研究的目的是在结直肠癌（CRC）的错配修复熟练模型中量化由单和双检查点抑制诱导的免疫应答。随着时间的推移监测肿瘤生长速率，并在组间进行比较。我们利用荧光激活的细胞分选来分析在用单一PD-1抑制或双重PD-1和CTLA-4抑制处理后的CD 8+和CD 4 + T细胞。此外，我们试图定量共抑制表面分子PD-1、LAG 3和TIM 3的表达。与单PD-1抑制或对照相比，双重检查点抑制与显著较慢的生长速率相关（p < 0.05）。无论是单药治疗还是双重检查点抑制都不会显著影响淋巴细胞的肿瘤浸润。在用双重抑制剂治疗后，浸润的CD 8 + T细胞表现出PD-1的表达显著降低，（1700 vs. 2545和2462; p < 0.05）和LAG 3（446.2对比694.4和707; p < 0.05），与对照组和抗PD-1组相比，沿着具有显著更多的TIM 3表达（12，611对比2961和4259; p < 0.05）。这些结果表明，抗CTLA-4和抗PD-1抗体的双重治疗通过抑制免疫抑制检查点显著抑制微卫星稳定CRC的生长。TIM 3的上调代表了一种潜在的逃逸机制，也是CRC未来联合免疫治疗的靶点。
Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.
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影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
DOI：
10.1158/1078-0432.ccr-16-3133
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
3.9
作者：
Ansa BE;Coughlin SS;Alema-Mensah E;Smith SA
通讯作者：
Smith SA
影响因子：
7.2
作者：
Du S;McCall N;Park K;Guan Q;Fontina P;Ertel A;Zhan T;Dicker AP;Lu B
通讯作者：
Lu B
DOI：
10.5114/wo.2018.73889
发表时间：
2018-03
期刊：
Contemporary oncology (Poznan, Poland)
影响因子：
--
作者：
Lugowska I;Teterycz P;Rutkowski P
通讯作者：
Rutkowski P