Abstract
Breast cancer is characterized by some types of heterogeneity, high aggressive behaviour, and low immunotherapeutic efficiency. Detailed immune stratification is a prerequisite for interpreting resistance to treatment and escape from immune control. Hence, the immune landscape of breast cancer needs further understanding. We systematically clustered breast cancer into six immune subtypes based on the mRNA expression patterns of immune signatures and comprehensively depicted their characteristics. The immunotherapeutic benefit score (ITBscore) was validated to be a superior predictor of the response to immunotherapy in cohorts from various datasets. Six distinct immune subtypes related to divergences in biological functions, signatures of immune or stromal cells, extent of the adaptive immune response, genomic events, and clinical prognostication were identified. These six subtypes were characterized as immunologically quiet, chemokine dominant, lymphocyte depleted, wounding dominant, innate immune dominant, and IFN-γ dominant and exhibited features of the tumor microenvironment (TME). The high ITBscore subgroup, characterized by a high proportion of M1 macrophages:M2 macrophages, an activated inflammatory response, and increased mutational burden (such as mutations in TP53, CDH1 and CENPE), indicated better immunotherapeutic benefits. A low proportion of tumor-infiltrating lymphocytes (TILs) and an inadequate response to immune treatment were associated with the low ITBscore subgroup, which was also associated with poor survival. Analyses of four cohorts treated with immune checkpoint inhibitors (ICIs) suggested that patients with a high ITBscore received significant therapeutic advantages and clinical benefits. Our work may facilitate the understanding of immune phenotypes in shaping different TME landscapes and guide precision immuno-oncology and immunotherapy strategies.
Highlights
Human breast cancer remains a threat to women’s health worldwide and is characterized by intra-tumoral heterogeneity with biological and clinical diverseness [1, 2]
By scoring 83 signatures and applying the cluster method, we identified five representative immune signatures (Figure 1A): “Module3_IFN_score”, representing the IFNgamma response [30], STAT1_19272155, illustrating chemokine signalling [31], G_SIGLEC9, representing myeloid cell activation involved in immune responses [32], HER2_Immune_PCA_18006808, representing the regulation of lymphocyte activation [33], and Troester_WoundSig_19887484, representing the negative regulation of angiogenesis [34]
IS2 was dominated by M1 macrophages and had the highest proliferation rate, with the highest homologous recombination deficiency
Summary
Human breast cancer remains a threat to women’s health worldwide and is characterized by intra-tumoral heterogeneity with biological and clinical diverseness [1, 2]. Different subtypes of breast cancer present distinct tumor microenvironment (TME) characteristics, especially adaptive immunity. The properties, immunoediting ability, and diversity of the T cell receptor (TCR) repertoire of the adaptive immune response have been explored [6,7,8,9], the extensive immune landscape of breast cancer has not been fully elucidated. Recent clinical trials have demonstrated that immunotherapies showed low efficiency in the entire population of breast cancer patients, especially those with triple-negative breast cancer (TNBC) [11]. Except for the fact that breast cancer exhibits similar immunologically silent properties, a low mutational burden, and fewer tumor-infiltrating lymphocytes (TILs) than some other cancers [12, 13], the lack of an immunogenomic approach for appropriate patient selection and precise prognostic biomarkers might be the mainspring for these discouraging results
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