Converging and evolving immuno-genomic routes toward immune escape in breast cancer

Juan Blanco-Heredia, Carla Anjos Souza, Juan L. Trincado, Maria Gonzalez-Cao, Samuel Gonçalves-Ribeiro, Sara Ruiz Gil, Dmytro Pravdyvets, Samandhy Cedeño, Maurizio Callari, Antonio Marra, Andrea M. Gazzo, Britta Weigelt, Fresia Pareja, Theodore Vougiouklakis, Achim A. Jungbluth, Rafael Rosell, Christian Brander, Francesc Tresserra, Jorge S. Reis-Filho, Daniel Guimarães Tiezzi, Nuria de la Iglesia, Holger Heyn and Leticia De Mattos-Arruda ()
Additional contact information
Juan Blanco-Heredia: Germans Trias i Pujol University Hospital
Carla Anjos Souza: Germans Trias i Pujol University Hospital
Juan L. Trincado: Centro Nacional de Análisis Genómico (CNAG)
Maria Gonzalez-Cao: Quironsalud Group
Samuel Gonçalves-Ribeiro: Vall d’Hebron University Hospital
Sara Ruiz Gil: Centro Nacional de Análisis Genómico (CNAG)
Dmytro Pravdyvets: Omniscope
Samandhy Cedeño: Germans Trias i Pujol University Hospital
Maurizio Callari: Cancer Research UK Cambridge Institute, Robinson Way
Antonio Marra: Memorial Sloan Kettering Cancer Center
Andrea M. Gazzo: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Fresia Pareja: Memorial Sloan Kettering Cancer Center
Theodore Vougiouklakis: Memorial Sloan Kettering Cancer Center
Achim A. Jungbluth: Memorial Sloan Kettering Cancer Center
Rafael Rosell: Quironsalud Group
Christian Brander: Germans Trias i Pujol University Hospital
Francesc Tresserra: Quironsalud Group
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center
Daniel Guimarães Tiezzi: Ribeirao Preto Medical School, University of Sao Paulo
Nuria de la Iglesia: Germans Trias i Pujol University Hospital
Holger Heyn: Centro Nacional de Análisis Genómico (CNAG)
Leticia De Mattos-Arruda: Germans Trias i Pujol University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

Date: 2024
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DOI: 10.1038/s41467-024-45292-1

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