抗がん剤が効かないとき、既存の薬剤を独自に組み合わせることで、標的になっていない免疫系を利用して闘いに参加できる可能性があります。 When cancer drugs fail, a unique combination of already existing drugs could harness an under-targeted part of the immune system to join the fight
2022-06-13 ペンシルベニア州立大学(PennState)
Nearly 100,000 adults in the United States will be diagnosed with invasive melanoma of the skin in 2022, according to the American Cancer Society. Credit: CasaraGuru, Getty Images. All Rights Reserved.
新しい研究によると、もう一つの免疫細胞であるナチュラルキラー細胞を利用することで、T細胞が機能しなくなったときの遅れを取り戻すことができ、さらにT細胞を再活性化してメラノーマ腫瘍を攻撃できる可能性があることが判明した。研究チームは、マウスでこのナチュラルキラー細胞を介した免疫を活性化する独自の併用薬戦略を特定した。個々の薬剤は臨床的に使用されているが、併用はされておらず、この併用がヒトに有効であることを実証する必要がまだある。
<関連情報>
- https://www.psu.edu/news/research/story/novel-drug-combo-activates-natural-killer-cell-immunity-destroy-cancer-cells/
- https://aacrjournals.org/cancerimmunolres/article-abstract/10/6/757/699031/Targeting-WEE1-AKT-Restores-p53-Dependent-Natural?redirectedFrom=fulltext
WEE1/AKTを標的とすることで、p53依存性のナチュラルキラー細胞の活性化が回復し、「冷たい」メラノーマに免疫チェックポイント阻害応答を誘導する。 Targeting WEE1/AKT Restores p53-Dependent Natural Killer–Cell Activation to Induce Immune Checkpoint Blockade Responses in “Cold” Melanoma
Saketh S. Dinavahi;Yu-Chi Chen;Kishore Punnath;Arthur Berg;Meenhard Herlyn;Momeneh Foroutan;Nicholas D. Huntington;Gavin P. Robertson
CancerImmunology Research Published:JUNE 03 2022
DOI:https://doi.org/10.1158/2326-6066.CIR-21-0587
Abstract
Immunotherapy has revolutionized cancer treatment. Unfortunately, most tumor types do not respond to immunotherapy due to a lack of immune infiltration or “cold” tumor microenvironment (TME), a contributing factor in treatment failure. Activation of the p53 pathway can increase apoptosis of cancer cells, leading to enhanced antigen presentation, and can stimulate natural killer (NK) cells through expression of stress ligands. Therefore, modulation of the p53 pathway in cancer cells with wild-type TP53 has the potential to enhance tumor immunogenicity to NK cells, produce an inflammatory TME, and ultimately lead to tumor regression. In this study, we report simultaneous targeting of the AKT/WEE1 pathways is a novel and tolerable approach to synergistically induce p53 activation to inhibit tumor development. This approach reduced the growth of melanoma cells and induced plasma membrane surface localization of the ER-resident protein calreticulin, an indicator of immunogenic cell death (ICD). Increase in ICD led to enhanced expression of stress ligands recognized by the activating NK-cell receptor NKG2D, promoting tumor lysis. WEE1/AKT inhibition resulted in recruitment and activation of immune cells, including NK cells, in the TME, triggering an inflammatory cascade that transformed the “cold” TME of B16F10 melanoma into a “hot” TME that responded to anti–programmed cell death protein 1 (anti–PD-1), resulting in complete regression of established tumors. These results suggest that AKT/WEE1 pathway inhibition is a potential approach to broaden the utility of class-leading anti–PD-1 therapies by enhancing p53-mediated, NK cell–dependent tumor inflammation and supports the translation of this novel approach to further improve response rates for metastatic melanoma.
