2023年10月30日，來自美國李·莫菲特癌癥中心和研究所Jose R. Conejo-Garcia團隊在《免疫》發表了發表了標題為“Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.”的研究成果，發現用二聚體IgA (dIgA)靶向細胞內癌蛋白可促進細胞質的排出和上皮癌的免疫介導控制。
據悉，dIgA可以通過IgA/IgM聚合免疫球蛋白受體(PIGR)在細胞內移動，PIGR主要在粘膜上皮上表達。
他們研究了dIgA靶向通常突變的細胞質致癌因子的能力。突變特異性的dIgA，而不是IgG，可以中和卵巢癌細胞內的KRASG12D，并將其從腫瘤細胞中驅逐出去。dIgA結合改變了KRASG12D的內體運輸，從在循環內體中的積累轉變為在dIgA轉運的早期/晚期內體中的聚集。在細胞培養實驗中，靶向KRASG12D的dIgA消除了腫瘤細胞的增殖。
在體內，KRASG12D特異性的dIgA1以依賴CD8+ T細胞的方式限制了KRASG12D突變的卵巢癌和肺癌的生長。IDH1R132H特異性的dIgA降低了結腸癌的生長，證明了與表面受體無關的細胞質癌驅動因子的有效靶向。dIgA靶向KRASG12D比小分子KRASG12D抑制劑更有效地限制腫瘤生長，支持該方法治療人類癌癥的潛力。
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.
文章來源：
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
