Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments
Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments
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DOI：
10.1101/2023.01.10.521547
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发表时间：
2023-01
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通讯作者：
Callum Beach;Dave MacLean;D. Majorova;S. Melemenidis;Dhanya K. Nambiar;Ryan K. Kim;Gabriel N. Valbuena;S. Guglietta;C. Krieg;Damavandi Mahnaz Darvish;Tatsuya Suwa;A. Easton;E. Domingo;E. Moon;D. Jiang;Yanyan Jiang;A. Koong;T. Woodruff;E. Graves;Timothy S. Maughan;S. J. Buczacki;M. Stucki;Q. Le;S. Leedham;A. Giaccia;M. Olcina
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作者：
Callum Beach;Dave MacLean;D. Majorova;S. Melemenidis;Dhanya K. Nambiar;Ryan K. Kim;Gabriel N. Valbuena;S. Guglietta;C. Krieg;Damavandi Mahnaz Darvish;Tatsuya Suwa;A. Easton;E. Domingo;E. Moon;D. Jiang;Yanyan Jiang;A. Koong;T. Woodruff;E. Graves;Timothy S. Maughan;S. J. Buczacki;M. Stucki;Q. Le;S. Leedham;A. Giaccia;M. Olcina
免疫抑制微环境导致肿瘤T细胞浸润不良，并与结直肠癌患者总存活率降低有关。如何提高对这些肿瘤的治疗反应仍然是一个挑战。使用一种综合筛查方法来识别癌症特异性的易损性，我们将补体受体C5aR1确定为一个可药物靶点，当被抑制时，即使在表现出免疫抑制特征和CD8+T细胞渗透不良的肿瘤中也能改善放射治疗。虽然C5aR1因其在免疫隔间中的作用而广为人知，但我们发现C5aR1也在恶性上皮细胞上强烈表达，突出了潜在的肿瘤细胞特异性功能。C5aR1靶向导致肿瘤而不是正常组织中依赖于NF-κB的细胞凋亡增加；这表明在恶性肿瘤细胞中，C5aR1主要调节细胞命运。总而言之，这些数据表明，补体基因表达增加是辐射后肿瘤应激反应的一部分，靶向C5aR1可以改善放射治疗，即使在具有免疫抑制特征的肿瘤中也是如此。
An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-κB-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.