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month download article/chapter investigator-initiated research grant kerry-ann mcdonald mutant-allele tumor heterogeneity intra-tumour heterogeneity real-world cohort utilizing t-cell exhaustion markers postoperative plasma sphingosine-1-phosphate inferring intra-tumor heterogeneity tamoxifen sensitivity-related microrna-342 triple-negative breast cancer intra-tumor genetic heterogeneity tumor-infiltrating immune cells aso author reflections cancer immunotherapy tumor microenvironment tumor heterogeneity correlates phd & eigo otsuji md cancer genome atlas single-cell genetic analysis privacy choices/manage cookies kazuaki takabe md full article pdf breast cancer patients anti-tumor cd8 complex cancer genomics human breast cancer invasive breast cancer pan-cancer analysis neck cancer patients ann surg oncol breast cancer res cytolytic activity score jessica young md article mcdonald tumour antigens pathology resource network breast cancer validated fatal breast cancer treatment resistance additional information publisher' triple-negative tumors shapes tumor heterogeneity cytolytic enzymes granzyme somatic dna alterations negative breast cancers research pathology services cancer immunol res natl cancer inst nat rev cancer

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• Intra-tumour heterogeneity: A looking glass for cancer?

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         headline:Tumor Heterogeneity Correlates with Less Immune Response and Worse Survival in Breast Cancer Patients
         description: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. 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. 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). 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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      description: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. 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. 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). 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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            name:The State University of New York
            address:
               name:Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, USA
               type:PostalAddress
            type:Organization
            name:Tokyo Medical University
            address:
               name:Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
               type:PostalAddress
            type:Organization
            name:Yokohama City University
            address:
               name:Department of Surgery, Yokohama City University, Yokohama, Japan
               type:PostalAddress
            type:Organization
            name:Niigata University Graduate School of Medical and Dental Sciences
            address:
               name:Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
               type:PostalAddress
            type:Organization
            name:Fukushima Medical University
            address:
               name:Department of Breast Surgery and Oncology, Fukushima Medical University, Fukushima, Japan
               type:PostalAddress
            type:Organization
            name:Roswell Park Cancer Institute
            address:
               name:Breast Oncology and Surgery, Roswell Park Cancer Institute, Buffalo, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
      name:Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Thoracic Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
      name:Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, USA
      name:Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, USA
      name:Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
      name:Department of Surgery, Yokohama City University, Yokohama, Japan
      name:Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
      name:Department of Breast Surgery and Oncology, Fukushima Medical University, Fukushima, Japan
      name:Breast Oncology and Surgery, Roswell Park Cancer Institute, Buffalo, USA
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