Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.
Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.
复制标题
DOI：
10.1053/j.gastro.2022.06.027
复制
发表时间：
2022-11
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
--
作者：
胰腺导管腺癌（PDAC）中的间质有助于其免疫抑制性质和治疗抗性。在此，我们试图通过细胞内和细胞外机制靶向多种基质组分来修饰信号传导并增强免疫治疗功效。用粘着斑激酶抑制剂（FAKi）、抗PD-1抗体和通过PEGPH 20降解的基质透明质酸（HA）处理PDAC的鼠肝转移同基因模型，以评估这些药剂及其组合的免疫和基质调节作用。结果显示，PEGPH 20对HA的降解和FAKi对磷酸化FAK表达的降低导致用抗PD-1抗体治疗的携带PDAC的小鼠的存活率提高。HA降解与FAKi和抗PD-1抗体组合增加T细胞浸润并改变T细胞表型朝向效应记忆T细胞。FAKi改变T细胞调节细胞因子的表达，并导致T细胞代谢的变化和效应T细胞特征的增加。HA降解与抗PD-1抗体和FAKi治疗的组合减少了粒细胞，包括粒细胞-MDSC，并减少了表达CXCR 4的骨髓细胞，特别是表达CXCR 4的粒细胞。抗CXCR 4抗体与FAKi和抗PD-1抗体组合显著降低PDAC肝转移模型中的转移率。这代表了第一项临床前研究，以确定靶向PDAC基质内的细胞内和细胞外组分的协同效应，并支持测试抗CXCR 4抗体与FAKi组合作为PDAC治疗策略。同时靶向胰腺癌中基质的细胞内和细胞外组分可以改变肿瘤微环境，从而改善免疫治疗反应。
The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-PD-1 antibody and stromal hyaluronan (HA) degradation by PEGPH20 to assess immune and stromal modulating effects of these agents and their combinations. The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype towards effector memory T-cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes including granulocytic-MDSCs and decreases CXCR4 expressing myeloid cells, particularly the CXCR4 expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy. Simultaneous targeting of both intracellular and extracellular components of the stroma in pancreatic cancer, can alter the tumor microenvironment, thereby improving immunotherapy response.
登录
查看更多内容
影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
DOI：
10.1158/1078-0432.ccr-15-2010
发表时间：
2016-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hingorani SR;Harris WP;Beck JT;Berdov BA;Wagner SA;Pshevlotsky EM;Tjulandin SA;Gladkov OA;Holcombe RF;Korn R;Raghunand N;Dychter S;Jiang P;Shepard HM;Devoe CE
通讯作者：
Devoe CE
影响因子：
7.3
作者：
Foley K;Rucki AA;Xiao Q;Zhou D;Leubner A;Mo G;Kleponis J;Wu AA;Sharma R;Jiang Q;Anders RA;Iacobuzio-Donahue CA;Hajjar KA;Maitra A;Jaffee EM;Zheng L
通讯作者：
Zheng L
影响因子：
24.5
作者：
Jacobetz MA;Chan DS;Neesse A;Bapiro TE;Cook N;Frese KK;Feig C;Nakagawa T;Caldwell ME;Zecchini HI;Lolkema MP;Jiang P;Kultti A;Thompson CB;Maneval DC;Jodrell DI;Frost GI;Shepard HM;Skepper JN;Tuveson DA
通讯作者：
Tuveson DA