Converging and evolving immuno-genomic routes toward immune escape in breast cancer.
Juan Blanco-HerediaCarla Anjos SouzaJuan L TrincadoMaria Gonzales CaoSamuel Gonçalves-RibeiroSara Ruiz GilDmytro PravdyvetsSamandhy CedeñoMaurizio CallariAntonio MarraAndrea M GazzoJorge S Reis-FilhoFresia ParejaTheodore VougiouklakisAchim A JungbluthRafael RosellChristian BranderFrancesc TresserraJorge Sergio Reis-FilhoDaniel Guimarães TiezziNuria de la IglesiaHolger HeynLeticia De Mattos-ArrudaPublished in: Nature communications (2024)
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.