肿瘤细胞治疗研究
英文原题：Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.
嵌合抗原受体（CAR）T 细胞免疫治疗是血液系统恶性肿瘤治疗的突破，但特异性不佳限制了其在实体瘤中的适用性。
嵌合抗原受体（CAR）T细胞免疫疗法是血液系统恶性肿瘤治疗的突破，但特异性不足限制了其在实体瘤中的应用。相比之下，天然T细胞的T细胞受体（TCR）能够区分表达新抗原的癌细胞与表达自身抗原的健康组织，但其抗肿瘤效能有限。本研究利用高通量平台，系统评估在同一CAR-T细胞中共表达TCR与CAR的影响。强TCR-抗原相互作用可增强CAR活化，而弱TCR-抗原相互作用则会主动拮抗CAR活化。数学建模捕捉了CAR-T细胞中的TCR-CAR串扰，研究者据此设计了双重TCR/CAR T细胞，分别靶向新抗原（HHAT L8F/p53 R175H）和人表皮生长因子受体2（HER2）配体。在人源化实体瘤小鼠模型中，与传统CAR-T细胞相比，这些细胞表现出更强抗癌活性，且对健康组织的毒性极低。因此，利用受体间既有的抑制性串扰，为设计更精准的癌症免疫疗法开辟了道路。
Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHAT L8F /p53 R175H ) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.
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