PO.IM01.08 · 免疫学
在PDX肉瘤模型中通过attIL12-TIL疗法消除肿瘤胶原以增强疗效的新机制
Novel mechanism for eliminating tumor collagens to boost efficacy by attIL12-TIL therapy in PDX sarcoma models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
各种类型的肿瘤靶向T细胞疗法一直蓬勃发展，但T细胞疗法受限于其无法穿透"充塞"于肿瘤内部及肿瘤/肿瘤细胞周围的胶原屏障。与正常人体组织相比，通过bulk RNAseq和Masson三色染色测定，肉瘤组织表现出显著更高密度的胶原和细胞外基质(ECM)。破坏肿瘤胶原意义重大，因为胶原不仅抑制T细胞，还参与细胞外基质的形成。在本研究中，我们首次使用三对自体肉瘤患者来源异种移植(PDX)与自体肿瘤浸润T细胞(TIL)模型，发现CCKAR在体外和体内直接促进肿瘤细胞的胶原产生。attIL12改造的TIL在体外和体内使CCKAR高表达的自体肿瘤细胞的胶原产生失能。这种attIL12-TIL诱导的肿瘤细胞源性胶原产生的破坏需要两条信号通路的同时相互作用：1)自体肿瘤细胞上被attIL12靶向的CSV，以及2)attIL12-TIL上的HLA-TCR；当任一相互作用被消除时，胶原产生和CCKAR表达均未被关闭。机制上，attIL12-TIL与自体肿瘤细胞之间的双信号激活协同诱导肿瘤内超高水平的IFNgamma产生，其与CCKAR下调相结合，通过抑制TGFbeta刺激的SMAD激活和CCKAR-AKT信号传导来降低胶原表达。降低肿瘤细胞的胶原表达显著增加了T细胞浸润，并改善了PDX肉瘤中的肿瘤生长抑制。本研究首次揭示了在免疫治疗耐药肉瘤中高表达的CCKAR可作为减少肿瘤胶原的新靶点。attIL12改造介导的胶原破坏逆转了TIL在体外扩增后丧失的肿瘤穿透功能，实现了单用TIL无法达到的肉瘤肿瘤消退。因此，这种attIL12-TIL疗法在增强高级别、富含胶原的肿瘤中的T细胞浸润方面具有巨大的临床潜力。
查看英文原文 English abstract
Tumor-targeted T-cell therapies of various types have been booming, but T-cell therapy is limited by its inability to penetrate the collagen barrier that “stuffed” within tumors and surrounding tumors/tumor cells. Compared to normal human tissues, sarcoma tissues exhibited significantly higher density of collagens and extracellular matrix (ECM) determined via bulk RNAseq and Masson's trichrome staining. The destruction of tumor collagen is significant because collagen does not only suppresse T cells but also contributes to the formation of the extracellular matrix. In this study, for the first time, we used three pairs of autologous sarcoma patient-derived xenograft (PDX) and autologous tumor infiltrating T cells (TILs) models to discover that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified TILs disabled collagen production from CCKAR-high autologous tumor cells in vitro and in vivo. This attIL12-TILs induced disruption of tumor cell derived collagen production required a simultaneous interaction between two signaling pathways: 1) the CSV on autologous tumor cells, which is targeted by attIL12, and 2) HLA-TCR on attIL12-TILs; when either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the dual signaling activation between attIL12-TILs and autologous tumor cells synergistically induced super high IFNgamma production in tumors, which in combination with CCKAR downregulation reduced collagen expression through suppression of both TGFbeta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T-cell infiltration and improved tumor growth inhibition in PDX sarcomas. This study revealed for the first time that CCKAR, which is highly expressed in immunotherapy resistant sarcomas, may serve as a novel target for reducing tumor collagens. attIL12 modification mediated collagen disrupting reversed the lost tumor penetration function of TILs post ex vivo expansion, resulting in sarcoma tumor regression that TILs alone fail to achieve. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T-cell infiltration in high-grade, collagen-rich tumors.
利益披露 Disclosure
J. Hu, None..
Y. Jin, None.