Kerry-Ann McDonald1, Tsutomu Kawaguchi1,2, Qianya Qi3, Xuan Peng3, Mariko Asaoka1, Jessica Young1, Mateusz Opyrchal4, Li Yan3, Santosh Patnaik5, Eigo Otsuji2, Kazuaki Takabe6,7,8,9,10,11,12. 1. Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 2. Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. 3. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 4. Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 5. Thoracic Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 6. Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Kazuaki.Takabe@roswellpark.org. 7. Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA. Kazuaki.Takabe@roswellpark.org. 8. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan. Kazuaki.Takabe@roswellpark.org. 9. Department of Surgery, Yokohama City University, Yokohama, Japan. Kazuaki.Takabe@roswellpark.org. 10. Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Kazuaki.Takabe@roswellpark.org. 11. Department of Breast Surgery and Oncology, Fukushima Medical University, Fukushima, Japan. Kazuaki.Takabe@roswellpark.org. 12. Breast Oncology and Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA. Kazuaki.Takabe@roswellpark.org.
Abstract
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.
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-tumorCD8 (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.
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