Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer.
Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer.
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DOI：
10.1136/jitc-2021-003549
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发表时间：
2022-01
影响因子：
10.9
通讯作者：
Bronte V
中科院分区：
文献类型：
--
作者：
De Sanctis F;Lamolinara A;Boschi F;Musiu C;Caligola S;Trovato R;Fiore A;Frusteri C;Anselmi C;Poffe O;Cestari T;Canè S;Sartoris S;Giugno R;Del Rosario G;Zappacosta B;Del Pizzo F;Fassan M;Dugnani E;Piemonti L;Bottani E;Decimo I;Paiella S;Salvia R;Lawlor RT;Corbo V;Park Y;Tuveson DA;Bassi C;Scarpa A;Iezzi M;Ugel S;Bronte V
胰腺导管腺癌（PDAC）是最致命的肿瘤之一，由于其强大的结缔组织增生，低免疫原性，并招募癌症条件，免疫调节髓样细胞。这些特征强烈限制了免疫疗法作为单一药物的成功，从而表明需要开发多靶向方法。其目标是促进T淋巴细胞在肿瘤环境中的浸润并中和癌症引发的免疫抑制，以增强基于免疫的治疗的治疗效果，例如抗癌过继细胞疗法（ACT）。我们研究了表达抗氧化酶1和一氧化氮合酶2的免疫抑制性骨髓细胞在建立活性氮类（RNS）依赖性化学屏障和塑造PDAC免疫景观中的作用。我们研究了药理学RNS干扰对克服肿瘤扩增的骨髓细胞的募集和免疫抑制活性的影响，这些细胞使胰腺癌对免疫治疗产生耐药性。PDAC进展的标志是髓样细胞的逐步浸润，其通过L-精氨酸通过脱氢酶1和诱导型一氧化氮合酶活性的不受控制的代谢来加强高度免疫抑制的微环境，导致产生大量活性氧和氮物质。骨髓抑制细胞和硝化酪氨酸（硝基酪氨酸，N-Ty）的广泛积累建立了RNS依赖性化学屏障，其损害T淋巴细胞的肿瘤浸润并限制过继免疫疗法的功效。用AT 38（水杨酸[3-（氨基羰基）氧化呋咱-4-基]甲酯）进行的药理学治疗将肿瘤微环境从促肿瘤重编程为抗肿瘤，其支持T淋巴细胞进入肿瘤核心内，并辅助ACT与端粒酶特异性细胞毒性T淋巴细胞的功效。通过消除异常RNS产生的肿瘤微环境重编程通过克服免疫抗性绕过PDAC中免疫疗法的当前限制。
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT). We examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy. PDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes. Tumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance.
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影响因子：
7.3
作者：
De Sanctis F;Sandri S;Ferrarini G;Pagliarello I;Sartoris S;Ugel S;Marigo I;Molon B;Bronte V
通讯作者：
Bronte V
DOI：
10.1158/1078-0432.ccr-11-0503
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Klebanoff CA;Gattinoni L;Palmer DC;Muranski P;Ji Y;Hinrichs CS;Borman ZA;Kerkar SP;Scott CD;Finkelstein SE;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
50.3
作者：
Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
50.3
作者：
Bear AS;Vonderheide RH;O'Hara MH
通讯作者：
O'Hara MH
影响因子：
20.3
作者：
Everts, Bart;Amiel, Eyal;Pearce, Edward J.
通讯作者：
Pearce, Edward J.