2023年10月30日，来自美国李·莫菲特癌症中心和研究所Jose R. Conejo-Garcia团队在《免疫》发表了发表了标题为“Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.”的研究成果，发现用二聚体IgA (dIgA)靶向细胞内癌蛋白可促进细胞质的排出和上皮癌的免疫介导控制。
据悉，dIgA可以通过IgA/IgM聚合免疫球蛋白受体(PIGR)在细胞内移动，PIGR主要在粘膜上皮上表达。
他们研究了dIgA靶向通常突变的细胞质致癌因子的能力。突变特异性的dIgA，而不是IgG，可以中和卵巢癌细胞内的KRASG12D，并将其从肿瘤细胞中驱逐出去。dIgA结合改变了KRASG12D的内体运输，从在循环内体中的积累转变为在dIgA转运的早期/晚期内体中的聚集。在细胞培养实验中，靶向KRASG12D的dIgA消除了肿瘤细胞的增殖。
在体内，KRASG12D特异性的dIgA1以依赖CD8+ T细胞的方式限制了KRASG12D突变的卵巢癌和肺癌的生长。IDH1R132H特异性的dIgA降低了结肠癌的生长，证明了与表面受体无关的细胞质癌驱动因子的有效靶向。dIgA靶向KRASG12D比小分子KRASG12D抑制剂更有效地限制肿瘤生长，支持该方法治疗人类癌症的潜力。
Highlights
•Dimeric IgA undergoes bona fide transcytosis through PIGR+ carcinoma cells
•Dimeric IgA specifically neutralizes mutated oncogenes inside tumor cells
•Oncodrivers are expelled outside tumor cells through altered endosomal trafficking
•Mutation-specific dimeric IgA specifically abrogates tumor growth in vivo
Summary
Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.
文章来源：
Subir Biswas, Gunjan Mandal, Carmen M. Anadon et al, Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers. DOI: 10.1016/j.immuni.2023.09.013 Immunity：最新IF：43.474
