The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.
The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.
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DOI：
10.1016/j.ccell.2021.11.002
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发表时间：
2022-01-10
期刊：
影响因子：
50.3
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Li H;Xiao Y;Li Q;Yao J;Yuan X;Zhang Y;Yin X;Saito Y;Fan H;Li P;Kuo WL;Halpin A;Gibbons DL;Yagita H;Zhao Z;Pang D;Ren G;Yee C;Lee JJ;Yu D
恢复抗肿瘤免疫力仍然是一个尚未解决的挑战。我们的回顾性分析显示，在免疫治疗期间服用抗组胺药的癌症患者的生存率显著提高。我们发现，组胺和组胺受体H1（HRH 1）在肿瘤微环境中经常增加，并诱导T细胞功能障碍。从机制上讲，HRH 1活化的巨噬细胞向M2样免疫抑制表型迁移，免疫检查点VISTA的表达增加，使T细胞功能失调。HRH 1基因敲除或抗组胺治疗逆转了巨噬细胞的免疫抑制，恢复了T细胞的细胞毒性功能，并恢复了免疫治疗反应。过敏，通过组胺-HRH 1轴，促进肿瘤生长，并诱导小鼠和人类的免疫治疗抗性。重要的是，与血浆组胺水平高的患者相比，血浆组胺水平低的癌症患者对抗PD-1治疗的客观应答率增加了两倍以上。总之，癌症患者中预先存在的过敏或高组胺水平可以抑制免疫治疗反应，并保证前瞻性地探索抗组胺药作为组合免疫治疗的佐剂。Li等人研究了癌细胞如何逃避免疫攻击和抵抗免疫疗法。癌细胞衍生的或过敏释放的组胺与肿瘤相关巨噬细胞上的HRH 1结合，抑制CD 8 + T细胞功能，加速肿瘤生长，并赋予免疫治疗抗性。H1-抗组胺药抵消组胺介导的免疫抑制，增强抗肿瘤免疫，并显着增强免疫治疗反应。
Reinvigoration of anti-tumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophages immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had more than tripled objective response rate to anti-PD-1 treatment compared to patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy. Li et al. investigate how cancer cells evade immune attack and resist immunotherapies. Cancer cell-derived or allergy-released histamine binds to HRH1 on tumor-associated macrophages that suppress CD8+ T cell function, accelerate tumor growth, and confer immunotherapy resistance. H1-antihistamines counteract histamine-mediated immunosuppression, reinforce anti-tumor immunity, and significantly enhance immunotherapy response.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
11.2
作者：
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通讯作者：
Merghoub T
影响因子：
82.9
作者：
Gao J;Ward JF;Pettaway CA;Shi LZ;Subudhi SK;Vence LM;Zhao H;Chen J;Chen H;Efstathiou E;Troncoso P;Allison JP;Logothetis CJ;Wistuba II;Sepulveda MA;Sun J;Wargo J;Blando J;Sharma P
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Sharma P
影响因子：
4.4
作者：
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通讯作者：
Mantovani, Alberto