缺氧與腫瘤免疫微環境相關:免疫治療在膀胱癌中的潛在應用

2023年12月，中國湖南中南大學湘雅第三醫院腫瘤科、湖南中醫藥大學醫學院病理教研室，湖南中醫藥大學附屬湖南省第二人民醫院呼吸科，中南大學湘雅第三醫院耳鼻喉頭頸外科，(Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China，Department of Pathology, Medical School, Hunan University of Chinese Medicine, Changsha, China，Department of Respiration, The Second People's Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, China，Department of Otolaryngology—Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China) Ke Cao老師研究團隊在《Cancer Medicine》上發表論文：

“Hypoxia is correlated with the tumor immune microenvironment: Potential application of immunotherapy in bladder cancer”

“缺氧與腫瘤免疫微環境相關:免疫治療在膀胱癌中的潛在應用”

Abstract：

Objective

Hypoxia, which can considerably affect the tumor microenvironment, hinders the use of immunotherapy in bladder cancer (BLCA). Therefore, we aimed to identify reliable hypoxia-related biomarkers to guide clinical immunotherapy in BLCA.

Methods

Using data downloaded from TCGA-BLCA cohort, we determined BLCA subtypes which divide 408 samples into different subtypes. Tumor immune infiltration levels of two clusters were quantified using ssGSEA, MCPcounter, EPIC, ESTIMATE, and TIMER algorithms. Next, we constructed a hypoxia score based on the expression of hypoxia-related genes. The IMvigor210 cohort and SubMap analysis were used to predict immunotherapeutic responses in patients with different hypoxia scores. Hub genes were screened using cytoscape, immunohistochemistry (IHC), and multispectral immunofluorescence were used to detect the spatial distribution of immune markers.

Results

Patients with BLCA were categorized into cluster1 (n?=?227) and Cluster2 (n?=?181). Immune infiltration and expression of immune markers were higher in Cluster1. Immune infiltration was also more obvious in the high-hypoxia score group which related to a better predicted response to immunotherapy. IHC, and multispectral immunofluorescence confirmed the importance of TLR8 in immune infiltration and immune phenotype.

Conclusions

BLCA subtype can evaluate the infiltration of immune cells in the tumor microenvironment of different patients. Hypoxia score in this study could effectively predict immunotherapeutic responses in patients with BLCA. TLR8 may be a potential target for clinical immunotherapy.

摘要：

目的

缺氧可顯著影響腫瘤微環境，阻礙膀胱癌(BLCA)免疫治療的應用。因此，研究人員旨在確定可靠的缺氧相關生物標志物來指導BLCA的臨床免疫治療。

方法

利用從TCGA-BLCA隊列中下載的數據，研究人員確定了BLCA亞型，將408個樣本劃分為不同的亞型。使用ssGSEA、MCPcounter、EPIC、ESTIMATE和TIMER算法量化兩個簇的腫瘤免疫浸潤水平。接下來，研究人員基于缺氧相關基因的表達構建了一個缺氧評分。IMvigor210隊列和SubMap分析用于預測不同缺氧評分患者的免疫治療反應。采用細胞鏡、免疫組化(IHC)技術篩選中樞基因，采用多光譜免疫熒光技術檢測免疫標記物的空間分布。

結果

BLCA患者分為cluster1 (n = 227)和Cluster2 (n = 181)。Cluster1免疫浸潤及免疫標志物表達較高。免疫浸潤在高缺氧評分組也更為明顯，這與更好的預測免疫治療反應有關。免疫組化和多光譜免疫熒光證實了TLR8在免疫浸潤和免疫表型中的重要作用。

結論

BLCA亞型可以評價不同患者腫瘤微環境中免疫細胞的浸潤情況。本研究中的缺氧評分可以有效預測BLCA患者的免疫治療反應。TLR8可能是臨床免疫治療的潛在靶點。

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