Habaz Inbar A, Ou Xuejin, Wang Nicole I, Schincaglia Angela, Shydlouskaya Valeryia, Mahendran Agetha, Martinez-Santiesteban Francisco M, Doolabi Dylan, Bao Yige, Movasseghi Ahmad R, Haruna Julius, Power Nicholas E, Scholl Timothy J, Huynh Melissa J, Sener Alp, Haeryfar S M Mansour
Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Chengdu, Sichuan, China.
J Immunother Cancer. 2025 Sep 15;13(9):e012496. doi: 10.1136/jitc-2025-012496.
Mucosa-associated invariant T (MAIT) cells represent a unique population of innate-like T lymphocytes capable of detecting non-peptide antigens in the context of monomorphic antigen-presenting molecules. Due to their abundance in barrier tissues, reactivity to local inflammatory cues, and cytotoxic and regulatory functions, MAIT cells are poised to shape the dynamics of various tumor microenvironments. Growing evidence suggests that MAIT cells can exert protumor and/or antitumor effects in cancers arising from or metastasizing to mucosal tissues. However, MAIT cell roles in bladder cancer (BCa) remains unclear.
To begin to identify MAIT cells in BCa, we stained bladder tumor biopsies for T cell receptor (TCR) Vα7.2 cells. We then refined a human MAIT cell signature, which enabled us to interrogate a bulk RNA sequencing dataset and conduct correlation analyses linking intratumoral MAIT cell abundance and mortality from BCa. To extend our work to an in vivo setting, we employed a clinically relevant mouse model in which B6-MAIT (MAIT-sufficient) and B6-MAIT (MAIT-deficient) mice were exposed to N-butyl-N-(4-hydroxybutyl)nitrosamine, a chemical carcinogen associated with tobacco smoke. In additional experiments, MAIT cells were functionally removed through acetyl-6-formylpterin (Ac-6-FP) administration. Effector and regulatory cell types were phenotyped by flow cytometry, and BCa tumor burden and progression were assessed by MRI and/or H&E and Ki67 staining.
TCR Vα7.2 cells were readily detectable in several BCa biopsies, and our bioinformatic analyses correlated heavier MAIT cell presence in BCa tumors with poorer overall survival. Similarly, we found higher tumor burdens in B6-MAIT mice than in or Ac-6-FP-treated animals. Bladder MAIT cells from tumor-bearing mice exhibited phenotypic MAIT17 bias based on transcription factors they harbored along with increased interleukin-17A and tumor necrosis factor-α production capacities upon stimulation. Finally, FoxP3 regulatory T (T) cell frequencies were elevated in mouse bladder tumors, likely contributing to an immunosuppressive tumor microenvironment, a finding that could be recapitulated in our transcriptomic studies on human BCa.
MAIT cells are abundant in BCa tumor microenvironments where they potentiate T cell accumulation and play protumor roles.
黏膜相关恒定T（MAIT）细胞代表一类独特的固有样T淋巴细胞群体，能够在单态抗原呈递分子的背景下检测非肽抗原。由于它们在屏障组织中数量丰富，对局部炎症信号有反应，并且具有细胞毒性和调节功能，MAIT细胞有望塑造各种肿瘤微环境的动态变化。越来越多的证据表明，MAIT细胞在起源于黏膜组织或转移至黏膜组织的癌症中可发挥促肿瘤和/或抗肿瘤作用。然而，MAIT细胞在膀胱癌（BCa）中的作用仍不清楚。
为了开始鉴定BCa中的MAIT细胞，我们对膀胱肿瘤活检组织进行T细胞受体（TCR）Vα7.2细胞染色。然后，我们完善了一种人类MAIT细胞特征，这使我们能够分析大量RNA测序数据集，并进行相关性分析，将肿瘤内MAIT细胞丰度与BCa死亡率联系起来。为了将我们的工作扩展到体内环境，我们采用了一种临床相关的小鼠模型，其中B6-MAIT（MAIT充足）和B6-MAIT（MAIT缺陷）小鼠暴露于N-丁基-N-（4-羟丁基）亚硝胺，一种与烟草烟雾相关的化学致癌物。在额外的实验中，通过给予乙酰-6-甲酰蝶呤（Ac-6-FP）在功能上去除MAIT细胞。通过流式细胞术对效应细胞和调节细胞类型进行表型分析，并通过MRI和/或苏木精-伊红（H&E）染色及Ki67染色评估BCa肿瘤负荷和进展情况。
在几份BCa活检组织中很容易检测到TCR Vα7.2细胞，我们的生物信息学分析表明，BCa肿瘤中MAIT细胞数量越多，总体生存率越低。同样，我们发现B6-MAIT小鼠的肿瘤负荷高于B6-MAIT或经Ac-6-FP处理的动物。来自荷瘤小鼠的膀胱MAIT细胞基于其所含转录因子表现出表型上的MAIT17偏向，并且在刺激后白细胞介素-17A和肿瘤坏死因子-α的产生能力增加。最后，在B6-MAIT小鼠膀胱肿瘤中，叉头框蛋白3调节性T（Treg）细胞频率升高，这可能导致免疫抑制性肿瘤微环境，这一发现可以在我们对人类BCa的转录组学研究中得到印证。
MAIT细胞在BCa肿瘤微环境中数量丰富，在其中它们促进T细胞积累并发挥促肿瘤作用。
