【原】乳腺癌改变免疫或免疫改变乳腺癌

　　众所周知，不同患者的肿瘤之间、同一患者的不同肿瘤之间各不相同，即所谓的异质性。不过，同一患者的同一肿瘤内部也可能存在异质性，意味着基因型、表现型或行为特征各不相同的癌细胞亚群共存于同一肿瘤。肿瘤异质性可以影响疾病的进展、转移和治疗耐药，但是与肿瘤浸润免疫细胞的相关性存在争议，有些人认为高异质性肿瘤可能产生吸引免疫细胞的新抗原，而其他人则认为免疫细胞产生选择压力（物竞天择，适者生存）形成肿瘤异质性。如同苏芮《一样的月光》歌词所唱：是我们改变了世界？还是世界改变了我和你？

　　2019年4月8日，美国乳腺外科医师学会和肿瘤外科学会《肿瘤外科学报》在线发表纽约州立大学布法罗（水牛城）分校、罗斯威尔帕克综合癌症中心、罗斯威尔帕克癌症研究所、日本京都府立医科大学、东京医科大学、横滨市立大学、新潟大学、福岛医科大学的研究报告，利用美国国家癌症研究所（NCI）癌症基因组图谱（TCGA）真实世界乳腺癌患者队列，分析了肿瘤异质性与免疫细胞以及乳腺癌患者生存结局之间的相关性。

　　该研究通过计算突变等位基因肿瘤异质性，推算肿瘤内部异质性。利用斯坦福大学CIBERSORT工具，分析免疫细胞组成。利用生存曲线，分析患者生存结局。

　　结果，肿瘤异质性较高与较低相比：

• 患者总生存结局显著较差（P=0.049）

• 雌激素受体阳性肿瘤较多（P=0.011）

• 非三阴性乳腺癌显著较多（P=0.01）

• 靶细胞溶解活性评分较低（P=0.0028）

• 抗肿瘤的杀伤型T细胞较少（P<0.013）

• 抗肿瘤的辅助型T细胞较少（P<0.00024）

• 促肿瘤的调节型T细胞较多（P<0.0004）

• 抑制T细胞的PDL1表达较低（P=0.0031）

• 抑制T细胞的IDO2表达较低（P=0.34）

• 抑制T细胞的ADORA2A表达较低（P=0.018）

• 抑制T细胞的VISTA表达较低（P=0.00013）

• 抑制T细胞的CCR4表达较低（P<0.00001）

• 溶解靶细胞的颗粒酶A表达较低（P=0.0056）

• 溶解靶细胞的穿孔素1表达较低（P=0.053）

　　因此，该研究结果表明，肿瘤异质性高与免疫细胞浸润较少、免疫应答激活较少、乳腺癌生存结局较差密切相关，证实了肿瘤浸润免疫细胞选择压力形成肿瘤异质性的观点。

Ann Surg Oncol. 2019 Apr 8. [Epub ahead of print]

Tumor Heterogeneity Correlates with Less Immune Response and Worse Survival in Breast Cancer Patients.

Kerry-Ann McDonald, Tsutomu Kawaguchi, Qianya Qi, Xuan Peng, Mariko Asaoka, Jessica Young, Mateusz Opyrchal, Li Yan, Santosh Patnaik, Eigo Otsuji, Kazuaki Takabe.

Roswell Park Comprehensive Cancer Center, Buffalo, USA; Kyoto Prefectural University of Medicine, Kyoto, Japan; The State University of New York, Buffalo, USA; Tokyo Medical University, Tokyo, Japan; Yokohama City University, Yokohama, Japan; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Fukushima Medical University, Fukushima, Japan; Roswell Park Cancer Institute, Buffalo, USA.

BACKGROUND: Intratumor heterogeneity implies that subpopulations of cancer cells that differ in genetic, phenotypic, or behavioral characteristics coexist in a single tumor (Ma in Breast Cancer Res Treat 162(1):39-48, 2017; Martelotto in Breast Cancer Res 16(3):210, 2014). Tumor heterogeneity drives progression, metastasis and treatment resistance, but its relationship with tumor infiltrating immune cells is a matter of debate, where some argue that tumors with high heterogeneity may generate neoantigens that attract immune cells, and others claim that immune cells provide selection pressure that shapes tumor heterogeneity (McGranahan et al. in Science 351(6280):1463-1469, 2016; McGranahan and Swanton in Cell 168(4):613-628, 2017). We sought to study the association between tumor heterogeneity and immune cells in a real-world cohort utilizing The Cancer Genome Atlas.

METHODS: Mutant allele tumor heterogeneity (MATH) was calculated to estimate intratumoral heterogeneity, and immune cell compositions were estimated using CIBERSORT. Survival analyses were demonstrated using Kaplan-Meir curves.

RESULTS: Tumors with high heterogeneity (high MATH) were associated with worse overall survival (p = 0.049), as well as estrogen receptor-positive (p = 0.011) and non-triple-negative tumors (p = 0.01). High MATH tumors were also associated with less infiltration of anti-tumor CD8 (p < 0.013) and CD4 T cells (p < 0.00024), more tumor-promoting regulatory T cells (p < 4e-04), lower expression of T-cell exhaustion markers, specifically PDL-1 (p = 0.0031), IDO2 (p = 0.34), ADORA2A (p = 0.018), VISTA (p = 0.00013), and CCR4 (p < 0.00001), lower expression of cytolytic enzymes granzyme A (p = 0.0056) and perforin 1 (p = 0.053), and low cytolytic activity score (p = 0.0028).

CONCLUSIONS: High heterogeneity tumors are associated with less immune cell infiltration, less activation of the immune response, and worse survival in breast cancer. Our results support the notion that tumor heterogeneity is shaped by selection pressure of tumor-infiltrating immune cells.

DOI: 10.1245/s10434-019-07338-3