Townsend Katelin N, Spowart Jaeline E, Huwait Hassan, Eshragh Sima, West Nathan R, Elrick Mary A, Kalloger Steve E, Anglesio Michael, Watson Peter H, Huntsman David G, Lum Julian J
Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
PLoS One. 2013 Dec 23;8(12):e82406. doi: 10.1371/journal.pone.0082406. eCollection 2013.
When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.
In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049-5.106); p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097-5.799); p = 0.0294].
Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.
当T细胞浸润肿瘤环境时，它们会遇到包括缺氧在内的众多代谢应激源。克服由导致这些应激源的肿瘤血管系统不足所带来的限制，可能是免疫细胞产生有效抗肿瘤反应的关键一步。我们试图确定肿瘤浸润淋巴细胞（TIL）的功能能力是否会受到肿瘤血管系统的影响，并将其与卵巢癌患者的生存率相关联。
在196例高级别浆液性卵巢肿瘤中，我们证实通过标志物CD31测量的肿瘤血管密度与患者疾病特异性生存率的提高相关。我们还发现，TIL标志物（CD8、CD4和叉头框P3（FoxP3））和T细胞功能标志物（颗粒酶B和T细胞限制性细胞内抗原-1（TIA-1））阳性的肿瘤与血管密度升高显著相关。在体外，缺氧的CD8 T细胞表现出细胞溶解活性降低、效应细胞因子分泌减少以及自噬上调。生存分析显示，与CD31低表达肿瘤中存在FoxP3表达细胞的患者相比，CD31高表达肿瘤中存在FoxP3表达细胞的患者疾病特异性生存率有显著提高[风险比：2.314（95%置信区间1.049 - 5.106）；p = 0.0377]。与VEGF低表达肿瘤中存在颗粒酶B阳性细胞的患者相比，VEGF高表达肿瘤中存在颗粒酶B阳性细胞的患者生存率有所提高[风险比：2.522（95%置信区间1.097 - 5.799）；p = 0.0294]。
总体而言，这些数据为制定旨在提高TIL对缺氧肿瘤条件的适应性和功能的策略提供了理论依据。
