The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer.
The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer.
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放射疗法和补体C3a抑制剂的组合增强了自然杀伤细胞对胰腺癌的功能。
DOI：
10.1158/2767-9764.crc-22-0069
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Giaccia, Amato J.
中科院分区：
文献类型：
--
作者：
Sodji, Quaovi H.;Nambiar, Dhanya K.;Viswanathan, Vignesh;von Eyben, Rie;Colburg, Deana;Binkley, Michael S.;Li, Caiyun G.;Olcina, Monica M.;Chang, Daniel T.;Le, Quynh-Thu;Giaccia, Amato J.
胰腺癌是最致命的癌症之一，目前的免疫治疗策略对其无效。在此，我们分析了癌症基因组图谱中胰腺癌样本肿瘤微环境的免疫细胞组成，发现肿瘤内自然杀伤（NK）细胞的存在与生存相关。随后的分析还表明，NK细胞从微环境中排除在高比例的临床胰腺癌和胰腺癌的临床前模型中。从机制上讲，NK细胞排斥部分受补体C3a及其受体信号传导调节。抑制C3a受体可增强胰腺癌同基因小鼠模型中的NK细胞浸润，导致肿瘤生长延迟。然而，由NK细胞介导的肿瘤生长抑制单独不足以使肿瘤完全消退，但当与放射疗法组合时增强。我们的研究结果表明，虽然C3a抑制是一种有前途的方法，以提高NK细胞为基础的免疫治疗胰腺癌，其与放射治疗的组合具有更大的治疗效益。免疫抑制剂对胰腺癌无效。我们发现，补体C3a的抑制增强了胰腺癌临床前模型中的NK细胞浸润，导致肿瘤生长延迟。这种作用通过放射疗法进一步增强，从而与单独的任一种疗法相比产生显著的抗肿瘤活性。
Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral natural killer (NK) cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiotherapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell–based immunotherapy against pancreatic cancer, its combination with radiotherapy holds greater therapeutic benefit. Immunotherapeutic agents are not effective against pancreatic cancer. We show that the inhibition of complement C3a enhances NK cell infiltration in preclinical models of pancreatic cancer, resulting in tumor growth delay. This effect is further potentiated by radiotherapy, thereby leading to significant antitumor activity compared with either therapy alone.
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影响因子：
11.5
作者：
Muntasell, Aura;Rojo, Federico;Albanell, Joan
通讯作者：
Albanell, Joan
影响因子：
10.1
作者：
Nandagopal, Saravanan;Li, Caiyun G.;Xu, Yu;Sodji, Quaovi H.;Graves, Edward E.;Giaccia, Amato J.
通讯作者：
Giaccia, Amato J.
影响因子：
4.7
作者：
Demaria S;Formenti SC
通讯作者：
Formenti SC
DOI：
10.1073/pnas.79.19.6003
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CHARRIAUT, C;SENIK, A;FRADE, R
通讯作者：
FRADE, R
影响因子：
4.6
作者：
Lee, A. T. J.;Chew, W.;Huang, P. H.
通讯作者：
Huang, P. H.