1. Converging and evolving immuno-genomic routes toward immune escape in breast cancer
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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