Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer.
Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer.
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DOI：
10.1136/jitc-2021-002917
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发表时间：
2021-11
影响因子：
10.9
通讯作者：
Pan CX
中科院分区：
文献类型：
--
作者：
Zhu S;Ma AH;Zhu Z;Adib E;Rao T;Li N;Ni K;Chittepu VCSR;Prabhala R;Garisto Risco J;Kwiatkowski D;Mouw K;Sonpavde G;Cheng F;Pan CX
免疫检查点阻断（ICB）在大约20%的晚期膀胱尿路上皮癌（aUC）患者中诱导持久的反应。超过50%的aUC沿着磷酸肌醇3-激酶（PI 3 K）途径具有沿着的基因组改变。本项目的目的是确定PI 3 K抑制和ICB联合治疗aUC的协同作用和作用机制。在癌症基因组图谱（TCGA）和癌症相关图谱数据库中检查了影响PI 3 K通路的改变。具有Pten缺失的人和小鼠细胞用于体外研究。使用携带同源肿瘤的C57 BL/6小鼠来确定泛-PI 3 K抑制、ICB和组合的体内活性、作用机制和继发性抗性。在TCGA中，57%的aUC发生了沿着PI 3 K通路的改变。PIK 3CA的CRISPR（成簇的规则间隔的短回文重复序列）敲除诱导细胞增殖的显著抑制（p=0.0046）。在体外，PI 3 K抑制抑制癌细胞生长、迁移和集落形成。Pan-PI 3 K抑制、抗程序性死亡1（aPD 1）治疗和联合治疗分别将具有PTEN缺失肿瘤的同基因小鼠的总生存期（OS）从对照的27天提高到48、37和65天。在肿瘤不含PI 3 K通路改变的小鼠中，联合给药延长了OS，但单次给药未延长OS。Pan-PI 3 K抑制显著上调树突状细胞中的CD 80、CD 86、MHC-I和MHC-II，并下调转化生长因子β途径，错误发现率调整的q值为0.001。干扰素α应答在aPD 1治疗（q值：<0.001）和联合治疗（q值：0.027）的情况下显著上调。与对照组相比，联合治疗增加了CD 8 + T细胞浸润（p=0.005），减少了Treg细胞浸润（p=0.036），并上调了多种免疫刺激细胞因子和颗粒酶B的表达（p<0.01）。继发性耐药与雷帕霉素靶蛋白（mTOR）通路和多个Sprr家族基因的上调有关。Pan-PI 3 K抑制和ICB的组合在具有或不具有活化的PI 3 K通路的aUC中具有显著的抗肿瘤作用，并且需要进一步的临床研究。这种组合产生了免疫刺激性肿瘤环境。继发性耐药性与mTOR途径和Sprr家族基因的上调相关。
Immune checkpoint blockade (ICB) induces durable response in approximately 20% of patients with advanced bladder urothelial cancer (aUC). Over 50% of aUCs harbor genomic alterations along the phosphoinositide 3-kinase (PI3K) pathway. The goal of this project was to determine the synergistic effects and mechanisms of action of PI3K inhibition and ICB combination in aUC. Alterations affecting the PI3K pathway were examined in The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map databases. Human and mouse cells with Pten deletion were used for in vitro studies. C57BL/6 mice carrying syngeneic tumors were used to determine in vivo activity, mechanisms of action and secondary resistance of pan-PI3K inhibition, ICB and combination. Alterations along the PI3K pathway occurred in 57% of aUCs in TCGA. CRISPR (clustered regularly interspaced short palindromic repeats) knockout of PIK3CA induced pronounced inhibition of cell proliferation (p=0.0046). PI3K inhibition suppressed cancer cell growth, migration and colony formation in vitro. Pan-PI3K inhibition, antiprogrammed death 1 (aPD1) therapy and combination improved the overall survival (OS) of syngeneic mice with PTEN-deleted tumors from 27 days of the control to 48, 37, and 65 days, respectively. In mice with tumors not containing a PI3K pathway alteration, OS was prolonged by the combination but not single treatments. Pan-PI3K inhibition significantly upregulated CD80, CD86, MHC-I, and MHC-II in dendritic cells, and downregulated the transforming growth factor beta pathway with a false discovery rate-adjusted q value of 0.001. Interferon alpha response was significantly upregulated with aPD1 therapy (q value: <0.001) and combination (q value: 0.027). Compared with the control, combination treatment increased CD8+ T-cell infiltration (p=0.005), decreased Treg-cell infiltration (p=0.036), and upregulated the expression of multiple immunostimulatory cytokines and granzyme B (p<0.01). Secondary resistance was associated with upregulation of the mammalian target of rapamycin (mTOR) pathway and multiple Sprr family genes. The combination Pan-PI3K inhibition and ICB has significant antitumor effects in aUC with or without activated PI3K pathway and warrants further clinical investigation. This combination creates an immunostimulatory tumor milieu. Secondary resistance is associated with upregulation of the mTOR pathway and Sprr family genes.