Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors.
Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors.
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细胞死亡诱导的免疫原性通过将免疫排斥转化为t细胞炎性膀胱肿瘤来增强化学免疫治疗反应。
DOI：
10.1038/s41467-022-29026-9
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发表时间：
2022-03-28
影响因子：
16.6
通讯作者：
Chan KS
中科院分区：
文献类型：
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作者：
Nikolos F;Hayashi K;Hoi XP;Alonzo ME;Mo Q;Kasabyan A;Furuya H;Trepel J;Di Vizio D;Guarnerio J;Theodorescu D;Rosser C;Apolo A;Galsky M;Chan KS
化学免疫疗法最近未能在晚期膀胱癌患者中表现出显著的临床益处;并且这种次优应答的潜在机制仍然难以捉摸。迄今为止，大多数研究都集中在肿瘤的内在特性，使他们“免疫排斥”。在这里，我们探索了一种替代的药物诱导机制，通过破坏免疫原性细胞死亡的发生来阻碍治疗反应。使用两种免疫排斥的肌肉浸润性膀胱癌（MIBC）同基因小鼠模型，我们表明，尽管表达活化标志物IFNγ和颗粒酶B，但基于铂的化疗减少了CD 8 + T细胞肿瘤浸润并限制了其抗肿瘤活性。从机制上讲，化疗诱导前列腺素E2（PGE 2）从垂死的癌细胞中释放，这是一种抑制性损伤相关分子模式（iDAMP），阻碍树突状细胞成熟。在药物阻断PGE 2释放后，CD 8 + T细胞变得杀肿瘤并显示上皮内浸润（或发炎）模式。这种“iDAMP阻断”方法与化疗协同作用，使膀胱肿瘤对抗PD 1免疫检查点抑制剂治疗敏感。这些发现为在未来的临床试验中评价这种药物组合提供了令人信服的理由。化学免疫疗法最近未能改善晚期肌层浸润性膀胱癌（MIBC）患者的客观反应。在这里，作者使用两种免疫排斥MIBC的小鼠模型，表明可以通过阻断考克斯-2/前列腺素E2轴来克服对化学免疫疗法的抵抗，从而重新激活抗肿瘤免疫应答。
Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded”. Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials. Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.
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影响因子：
11.2
作者：
Ho PL;Lay EJ;Jian W;Parra D;Chan KS
通讯作者：
Chan KS
DOI：
10.1158/1078-0432.ccr-19-1321
发表时间：
2020-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Garris CS;Luke JJ
通讯作者：
Luke JJ
影响因子：
158.5
作者：
Grossman, HB;Natale, RB;Crawford, ED
通讯作者：
Crawford, ED
影响因子：
6.4
作者：
Hayashi K;Nikolos F;Chan KS
通讯作者：
Chan KS
影响因子：
23.4
作者：
Galsky, Matthew D.;Wang, Huan;Uzilov, Andrew V.
通讯作者：
Uzilov, Andrew V.