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

• Published in: Nature communications Vol. 15; no. 1; pp. 1302 - 18
• Main Authors: Blanco-Heredia, Juan, Souza, Carla Anjos, Trincado, Juan L., Gonzalez-Cao, Maria, Gonçalves-Ribeiro, Samuel, Gil, Sara Ruiz, Pravdyvets, Dmytro, Cedeño, Samandhy, Callari, Maurizio, Marra, Antonio, Gazzo, Andrea M., Weigelt, Britta, Pareja, Fresia, Vougiouklakis, Theodore, Jungbluth, Achim A., Rosell, Rafael, Brander, Christian, Tresserra, Francesc, Reis-Filho, Jorge S., Tiezzi, Daniel Guimarães, de la Iglesia, Nuria, Heyn, Holger, De Mattos-Arruda, Leticia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/23; 38/39; 38/77; 38/91; 45; 45/23; 631/208/212; 631/250/2161; 631/67/1347; 82/51; Anticancer properties; Antigen presentation; Antitumor activity; Blood; Breast cancer; Breast Neoplasms - genetics; Cell interactions; Clocks; Convergence; Cytotoxicity; Female; Genomics; Genomics - methods; Heterogeneity; Humanities and Social Sciences; Humans; Immune evasion; Immune response; Immune system; Immunological memory; Lymphocytes; Lymphocytes T; Memory cells; Metastases; Metastasis; Microenvironments; multidisciplinary; Peripheral blood; Science; Science (multidisciplinary); Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45292-1

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. Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.