Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?
Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?
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DOI：
10.3390/cancers13143415
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发表时间：
2021-07-08
期刊：
影响因子：
5.2
通讯作者：
Nghiem P
中科院分区：
文献类型：
--
作者：
Goff PH;Bhakuni R;Pulliam T;Lee JH;Hall ET;Nghiem P
免疫疗法已经彻底改变了晚期癌症的管理;然而，由于许多癌症对免疫检查点抑制剂具有抗性，并非所有患者都受益。为了支持快速生长，恶性细胞经常绕过细胞周期检查点，这些检查点通常确保细胞分裂前的高保真DNA复制。因此，癌细胞（缺乏早期细胞周期检查点）处于高复制压力下，并且更严重地依赖于DNA损伤反应（DDR）来生存和生长。DDR途径是长期公认的抗肿瘤靶点。最近，临床前研究已经证明了这些途径和免疫系统之间的意想不到的串扰。在这里，我们讨论了新出现的证据连接细胞周期生物学和DDR的先天性和适应性免疫。我们提出了一个理由，为什么默克尔细胞癌可以作为一个范例，研究DDR抑制剂作为新的代理，以克服抵抗程序性细胞死亡-1（PD-1）通路阻断。 对免疫疗法有抗性的转移性癌症需要新的管理策略。DNA损伤反应（DDR）蛋白，包括ATR（ataxia telangiectasia and Rad 3-related）、ATM（ataxia telangiectasia mutated）和DNA-PK（DNA-dependent protein kinase），几十年来一直是有希望的治疗靶点。特异性、有效的DDR抑制剂（DDRi）最近进入临床试验。令人惊讶的是，临床前研究现在已经表明，DDRi可以刺激抗肿瘤免疫以增强免疫治疗。DDRi如何促进抗肿瘤免疫的机制尚未得到很好的理解;然而，早期的证据表明，它们可以增强免疫原性细胞死亡，以招募和激活抗原呈递细胞，从而引发适应性免疫应答。默克尔细胞癌（MCC）非常适合测试这些概念。它具有固有的免疫原性，因为约50%的晚期MCC患者持续受益于免疫治疗，使MCC成为最具反应性的实体瘤之一。作为典型的神经内分泌癌，p53和Rb的功能障碍伴随Myc的上调导致MCC的非常快速的生长。这表明高复制应激和对DDRi和DNA损伤剂的易感性。事实上，MCC肿瘤是特别放射敏感的。鉴于其固有的免疫原性，细胞周期检查点缺陷和对DNA损伤的敏感性，MCC可能是测试靶向DDR检查点和免疫检查点的交叉点是否可以帮助免疫治疗难治性癌症患者的理想选择。
Immunotherapies have revolutionized the management of advanced stage cancer; however, not all patients benefit given many cancers are resistant to immune checkpoint inhibitors. To support rapid growth, malignant cells frequently bypass the cell cycle checkpoints that normally ensure high-fidelity DNA replication prior to cell division. Therefore, cancer cells (lacking early cell cycle checkpoints) are under high replication stress and rely more heavily on the DNA damage response (DDR) for survival and growth. DDR pathways are long-recognized anti-neoplastic targets. Recently, preclinical studies have demonstrated unexpected crosstalk between these pathways and the immune system. Here, we discuss emerging evidence linking cell cycle biology and the DDR to innate and adaptive immunity. We present a rationale for why Merkel cell carcinoma could serve as a paradigm for studying DDR inhibitors as novel agents to overcome resistance to programmed cell death-1 (PD-1) pathway blockade. Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.
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DOI：
10.1158/1078-0432.ccr-12-3408
发表时间：
2013-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Biddlestone-Thorpe L;Sajjad M;Rosenberg E;Beckta JM;Valerie NC;Tokarz M;Adams BR;Wagner AF;Khalil A;Gilfor D;Golding SE;Deb S;Temesi DG;Lau A;O'Connor MJ;Choe KS;Parada LF;Lim SK;Mukhopadhyay ND;Valerie K
通讯作者：
Valerie K
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A
影响因子：
28.4
作者：
D'Angelo, Sandra P.;Russell, Jeffery;Kaufman, Howard L.
通讯作者：
Kaufman, Howard L.
影响因子：
11.2
作者：
Combes, Eve;Andrade, Augusto F.;Gongora, Celine
通讯作者：
Gongora, Celine