Enhancing antitumor immunity and achieving tumor eradication with IL11RA mRNA immunotherapy

作者全名：Rehman, Adeel ur; Wang, Zhihuai; Qin, Qianshan; Zhang, Xiaojing; Akhtar, Aleena; Liu, Hanyang; Mao, Binli; Khan, Naveed; Tang, Liming; Li, Xiaosong

作者地址：[Rehman, Adeel ur; Akhtar, Aleena; Mao, Binli; Li, Xiaosong] Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China; [Rehman, Adeel ur; Li, Xiaosong] Chongqing Med Univ, Inst Brain Sci & Dis, Key Lab Major Brain Dis & Aging Res, Minist Educ, Chongqing 400016, Peoples R China; [Wang, Zhihuai; Tang, Liming] Nanjing Med Univ, Changzhou 2 Peoples Hosp, Dept Gen Surg, Changzhou 213000, Jiangsu, Peoples R China; [Qin, Qianshan; Zhang, Xiaojing] Suzhou Abogen Biosci Co Ltd, Suzhou 215123, Jiangsu, Peoples R China; [Liu, Hanyang] Virchow Campus, Charite Univ Med Ctr, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany; [Liu, Hanyang] Mol Canc Res Ctr, D-13353 Berlin, Germany; [Khan, Naveed] Kyung Hee Univ, Grad Sch Green Bio Sci, Yongin 17104, South Korea

通信作者：Rehman, AU; Li, XS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China.; Rehman, AU; Li, XS (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Key Lab Major Brain Dis & Aging Res, Minist Educ, Chongqing 400016, Peoples R China.

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001240350500001

JCR分区：Q1

影响因子：4.8

年份：2024

卷号：134

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Cancer immunotherapy; mRNA immunotherapy; Interleukin therapy; mRNA synthesis; Cytokine therapy; IL11RA mRNA Therapy; mRNA-based therapies

摘要：Current methods for delivering genes to target tumors face significant challenges, including off-target effects and immune responses against delivery vectors. In this study, we developed a novel approach using messenger RNA (mRNA) to encode IL11RA for local immunotherapy, aiming to harness the immune system to combat tumors. Our research uncovered a compelling correlation between IL11RA expression and CD8 + T cell levels across multiple tumor types, with elevated IL11RA expression correlating with improved overall survival. Examination of the Pan-Cancer Atlas dataset showed a significant reduction in IL11RA expression in various cancer types compared to normal tissue, raising questions about its potential role in tumorigenesis. To achieve efficient in vivo expression of IL11RA, we synthesized two mRNA sequences mimicking the wild-type protein. These mRNA sequences were formulated and capped to ensure effective delivery, resulting in robust expression within tumor sites. Our investigation into IL11RA mRNA therapy demonstrated its effectiveness in controlling tumor growth when administered both intratumorally and intravenously in mouse models. Additionally, IL11RA mRNA treatment significantly stimulated the expansion of CD8 + T cells within tumors, draining lymph nodes, and the spleen. Transcriptome analysis revealed distinct transcriptional patterns associated with T cell functions. Using multiple deconvolution algorithms, we found substantial infiltration of CD8 + T cells following IL11RA mRNA treatment, highlighting its immunomodulatory effects within the tumor microenvironment. In conclusion, IL11RA mRNA therapy presents a promising strategy for tumor regression with potential immunomodulatory effects and clinical implications for improved survival outcomes.

基金机构：Natural Science Foundation of Chongqing China [2023NSCQ-LZX0104]; Chongqing Science and Health Joint Medical High-end Talent Project [2022GDRC012]; Chongqing Biomedical R & D Major Special Project [CSTB2022TIAD-STX0013]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K202100402]; CQMU Program for Youth Innovation in Future Medicine [W0073]; Changzhou Second People's Hospital Full-time Post-Doctoral Research Startup Fund [BSH202012]

基金资助正文：We are grateful for the financial support received from various sources, including the Natural Science Foundation of Chongqing China (Grant No. 2023NSCQ-LZX0104) , Chongqing Science and Health Joint Medical High-end Talent Project (Grant No. 2022GDRC012) , Chongqing Biomedical R & D Major Special Project (Grant No. CSTB2022TIAD-STX0013) , Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202100402) , CQMU Program for Youth Innovation in Future Medicine (Grant No. W0073) , and Changzhou Second People's Hospital Full-time Post-Doctoral Research Startup Fund BSH202012.