Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance.
Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance.
复制标题
胰腺导管腺癌的下一代免疫治疗：免疫抵抗的导航途径。
DOI：
10.1007/s10555-021-09981-3
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发表时间：
2021-09
影响因子：
9.2
通讯作者：
Azad, Nilofer
中科院分区：
文献类型：
--
作者：
Heumann, Thatcher;Azad, Nilofer
关键词：
迄今为止，免疫检查点抑制剂的使用已被证明在晚期胰腺导管腺癌患者中基本无效。低肿瘤抗原性、免疫活化缺陷沿着排斥性和抑制性肿瘤微环境的组合导致对宿主防御性的抗性。然而，对这些免疫逃逸和抑制机制的深入理解导致了新的分子靶点和治疗策略的发现，这些靶点和治疗策略可能是期待已久的治疗突破的关键。在这篇综述中，我们描述了现代免疫治疗的肿瘤内在和微环境障碍，研究了新的基于免疫的靶向方式，总结了相关的临床前研究结果和人类经验，最后，讨论了克服胰腺癌免疫耐药的新的协同方法。除了检查点抑制之外，免疫激动剂和抗肿瘤疫苗代表了通过激活和扩增抗肿瘤免疫效应物来刺激宿主应答的有前景的策略。现成的自然杀伤细胞疗法可能提供绕过下调的肿瘤抗原呈递的有效方法。与此同时，复杂的靶向肿瘤和肿瘤相关免疫细胞之间的串扰可能导致增强的免疫浸润和抗肿瘤淋巴细胞的存活。未来的多模式治疗策略涉及免疫引发/激活，肿瘤微环境重编程和免疫检查点阻断，可能有助于将胰腺癌转化为免疫原性肿瘤。
To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of anti-tumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.
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影响因子：
8.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Candido JB;Morton JP;Bailey P;Campbell AD;Karim SA;Jamieson T;Lapienyte L;Gopinathan A;Clark W;McGhee EJ;Wang J;Escorcio-Correia M;Zollinger R;Roshani R;Drew L;Rishi L;Arkell R;Evans TRJ;Nixon C;Jodrell DI;Wilkinson RW;Biankin AV;Barry ST;Balkwill FR;Sansom OJ
通讯作者：
Sansom OJ
影响因子：
11.2
作者：
Allegrezza, Michael J.;Rutkowski, Melanie R.;Conejo-Garcia, Jose R.
通讯作者：
Conejo-Garcia, Jose R.
影响因子：
8.8
作者：
Bramhall, SR;Schulz, J;Nemunaitis, J;Brown, PD;Baillet, M;Buckels, JAC
通讯作者：
Buckels, JAC
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM