Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients.
Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients.
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DOI：
10.4049/jimmunol.1201529
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Fong L
中科院分区：
文献类型：
--
作者：
Kwek SS;Dao V;Roy R;Hou Y;Alajajian D;Simko JP;Small EJ;Fong L
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）是活化T细胞上的表面受体，其递送抑制信号，充当免疫检查点。用抗CTLA-4抗体治疗可以诱导对不同恶性肿瘤的临床应答，但诱导的抗原特异性识别的性质在很大程度上是未知的。使用超过8000人类蛋白质点的微阵列，我们评估了由CTLA-4阻断剂和粒细胞巨噬细胞集落刺激因子（GM-CSF）治疗调节的抗体应答的多样性。我们发现，临床上对治疗有反应的晚期前列腺癌患者也比无反应者对更高数量的抗原产生增强的抗体反应。这些诱导的抗体应答靶向抗原，与无应答者相比，临床应答者中更可能存在预先存在的抗体。大多数抗体应答是患者特异性的，但也检测到针对临床应答者之间共享的抗原的免疫应答。这些共有抗原之一是p21激活激酶6（Pak 6），其在前列腺癌中表达，并且还诱导了对CD 4 + T细胞的应答。此外，用Pak 6免疫在小鼠肿瘤模型中可以是免疫原性和保护性的。这些结果表明，免疫检查点阻断调节对个体化和共享抗原的抗原特异性应答，其中一些可以介导抗肿瘤应答。
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a surface receptor on activated T cells that delivers an inhibitory signal, serving as an immune checkpoint. Treatment with anti-CTLA-4 antibodies can induce clinical responses to different malignancies, but the nature of the induced antigen-specific recognition is largely unknown. Using microarrays spotted with over 8000 human proteins, we assessed the diversity of antibody responses modulated by treatment with CTLA-4-blockade and granulocyte macrophage colony-stimulating factor (GM-CSF). We find that advanced prostate cancer patients who clinically respond to treatment also develop enhanced antibody responses to a higher number of antigens than non-responders. These induced antibody responses targeted antigens to which preexisting antibodies are more likely to be present in the clinical responders compared to non-responders. The majority of antibody responses are patient-specific, but immune responses against antigens shared among clinical responders are also detected. One of these shared antigens is p21-activated kinase 6 (Pak6), which is expressed in prostate cancer and to which CD4+ T cell responses were also induced. Moreover, immunization with Pak6 can be both immunogenic and protective in mouse tumor models. These results demonstrate that immune checkpoint blockade modulates antigen-specific responses to both individualized and shared antigens, some of which can mediate anti-tumor responses.
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影响因子：
50.3
作者：
Taylor BS;Schultz N;Hieronymus H;Gopalan A;Xiao Y;Carver BS;Arora VK;Kaushik P;Cerami E;Reva B;Antipin Y;Mitsiades N;Landers T;Dolgalev I;Major JE;Wilson M;Socci ND;Lash AE;Heguy A;Eastham JA;Scher HI;Reuter VE;Scardino PT;Sander C;Sawyers CL;Gerald WL
通讯作者：
Gerald WL
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4.8
作者：
Yang, F;Lio, XY;Sun, Z
通讯作者：
Sun, Z
影响因子：
4.4
作者：
Hernández, J;Ko, A;Sherman, LA
通讯作者：
Sherman, LA
DOI：
10.1073/pnas.0810114105
发表时间：
2008-12-23
影响因子：
11.1
作者：
Yuan, Jianda;Gnjatic, Sacha;Wolchok, Jedd D.
通讯作者：
Wolchok, Jedd D.