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1.
Acta Oncol ; 63: 359-367, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38779867

RESUMO

BACKGROUND: The tumor microenvironment significantly influences breast cancer development, progression, and metastasis. Various immune cell populations, including T cells, B cells, NK cells, and myeloid cells exhibit diverse functions in different breast cancer subtypes, contributing to both anti-tumor and pro-tumor activities. PURPOSE: This review provides an overview of the predominant immune cell populations in breast cancer subtypes, elucidating their suppressive and prognostic effects. We aim to outline the role of the immune microenvironment from normal breast tissue to invasive cancer and distant metastasis. METHODS: A comprehensive literature review was conducted to analyze the involvement of immune cells throughout breast cancer progression. RESULTS: In breast cancer, tumors exhibit increased immune cell infiltration compared to normal tissue. Variations exist across subtypes, with higher levels observed in triple-negative and HER2+ tumors are linked to better survival. In contrast,  ER+ tumors display lower immune infiltration, associated with poorer outcomes. Furthermore, metastatic sites commonly exhibit a more immunosuppressive microenvironment. CONCLUSION: Understanding the complex interaction between tumor and immune cells during breast cancer progression is essential for future research and the development of immune-based strategies. This comprehensive understanding may pave the way for more effective treatment approaches and improved patients outcomes.


Assuntos
Neoplasias da Mama , Progressão da Doença , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Prognóstico , Linfócitos do Interstício Tumoral/imunologia , Células Matadoras Naturais/imunologia
2.
Mol Oncol ; 16(1): 88-103, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165864

RESUMO

Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single-cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B-cell and natural killer (NK)-cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T-cell immunoreceptor with Ig and ITIM domains)-positive T cells with suppressed TCR signaling compared with non-metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T-cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos , Feminino , Humanos , Terapia de Imunossupressão , Linfonodos/patologia , Melanoma , Neoplasias Cutâneas , Subpopulações de Linfócitos T/patologia , Melanoma Maligno Cutâneo
3.
Math Med Biol ; 36(1): 93-112, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29452382

RESUMO

Intra-tumour phenotypic heterogeneity limits accuracy of clinical diagnostics and hampers the efficiency of anti-cancer therapies. Dealing with this cellular heterogeneity requires adequate understanding of its sources, which is extremely difficult, as phenotypes of tumour cells integrate hardwired (epi)mutational differences with the dynamic responses to microenvironmental cues. The later comes in form of both direct physical interactions, as well as inputs from gradients of secreted signalling molecules. Furthermore, tumour cells can not only receive microenvironmental cues, but also produce them. Despite high biological and clinical importance of understanding spatial aspects of paracrine signaling, adequate research tools are largely lacking. Here, a partial differential equation (PDE)-based mathematical model is developed that mimics the process of cell ablation. This model suggests how each cell might contribute to the microenvironment by either absorbing or secreting diffusible factors, and quantifies the extent to which observed intensities can be explained via diffusion-mediated signalling. The model allows for the separation of phenotypic responses to signalling gradients within tumour microenvironments from the combined influence of responses mediated by direct physical contact and hardwired (epi)genetic differences. The method is applied to a multi-channel immunofluorescence in situ hybridisation (iFISH)-stained breast cancer histological specimen, and correlations are investigated between: HER2 gene amplification, HER2 protein expression and cell interaction with the diffusible microenvironment. This approach allows partial deconvolution of the complex inputs that shape phenotypic heterogeneity of tumour cells and identifies cells that significantly impact gradients of signalling molecules.


Assuntos
Modelos Biológicos , Comunicação Parácrina/fisiologia , Microambiente Tumoral/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Simulação por Computador , Feminino , Amplificação de Genes , Técnicas Histológicas , Humanos , Hibridização in Situ Fluorescente , Conceitos Matemáticos , Mutação , Comunicação Parácrina/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais/fisiologia , Microambiente Tumoral/genética
4.
Nat Genet ; 49(3): 341-348, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28112740

RESUMO

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.


Assuntos
Neoplasias da Mama/genética , Loci Gênicos/genética , Mutação/genética , Sequências Reguladoras de Ácido Nucleico/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Feminino , Expressão Gênica/genética , Genoma/genética , Humanos , Transcriptoma/genética
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