The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

Abstract

Heterogeneity in breast carcinomas can be appreciated at various levels, from morphology to molecular alterations, and there are well-known genotypic-phenotypic correlations. Clinical decision-making is strictly focused on the evaluation of tumor cells and is based on the assessment of hormone receptors and of the HER2 status, by means of a combination of immunohistochemical and in situ hybridization techniques. The tumor microenvironment (TME) also shows a multifaceted nature stemming from the different actors populating the intratumoral and the peritumoral stroma of breast carcinomas. Of note, we have now evidence that tumor-infiltrating lymphocytes (TILs) are clinically meaningful as their quantification in the intratumoral stroma strongly correlates with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. Nevertheless, TILs are just one of the many actors orchestrating the complexity of the TME, which is populated by immune and non-immune cells (cancer-associated fibroblasts, cancer-associated adipocytes), as well as non-cellular components such as chemical inflammation mediators. In this review article we will overview the main features of the distinct cell compartments by discussing (i) the potential impact the TME may have on the prognostic stratification of breast cancers and (ii) the possible predictive value of some markers in the context of immunotherapy in light of the recent results of phase III studies in advanced and early triple-negative breast cancer patients.

Keywords: Breast cancer; Cancer-associated fibroblasts; Immune cells; Immunotherapy; Ligand 1 of programmed cell death protein 1; Mutational load; Tumor-infiltrating lymphocytes.

Fig. 1

An overview of the heterogeneity of stromal features across different breast carcinomas, including special histological types. a An example of immune-enriched cancer (so-called lymphocyte-predominant breast cancer) with >90% of stroma occupied by tumor-infiltrating lymphocytes (TILs): the tumor cells aggregate in a solid growth pattern and show high nuclear grade. b A well-differentiated tubular carcinoma showing dense fibroblastic stroma and rare TILs interspersed in the intratumoral stroma (<5%). c An NST (no special type) carcinoma displaying a dense fibrosclerotic immune-desert stroma. d An example of intratumor heterogeneity in breast cancer with a mixed carcinoma showing opposite stromal features in the two components: fibrosclerotic stroma in the NST component colliding with the typical spongy stroma of the micropapillary component (inset). e, f The unique stroma of mucinous carcinomas is composed by a lake of mucin, which is typically immune depleted and comprises tiny vessels (arrows).

Fig. 2

The tumor microenvironment (TME) in breast carcinomas. The picture summarizes the different cellular immune and non-cellular components of the TME in breast carcinomas. Tumor-infiltrating lymphocytes (TILs) are mainly represented by T-cells (CD3+) and include CD4+, CD8+ and T-regulatory cells (Treg). A minor component of TILs is represented by plasma cells and B-cells, usually found in tertiary lymphoid structures (TLS) with CD4+ and CD8+ T-cells and dendritic cells. Natural killer (NK) cells secrete cytokines such as TNF-α (tumor necrosis factor) and interferon-γ (IFN-γ). Tumor-associated macrophages (TAMs) are able to polarize into different phenotypes, M1 and M2. Tumor-associated neutrophils (TANs) can polarize into two distinct subtypes: N1 TANs and N2 TANs. TANs are able to release neutrophil elastase. In addition, neutrophil-derived oncostatin M, released by granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated TANs, can induce breast cancer cell detachment. Cancer-associated fibroblasts (CAFs) are classified into four subtypes (CAF-S1 to CAF-S4). CAF-S1 and CAF-S4 types are intratumoral CAFs, CAF-S3 are representative of the extratumoral stroma and CAF-S2 are equally distributed in both environments. Cancer-associated adipocytes (CAAs) are involved in tumor progression, metastasis and therapy resistance by secretion of adipokine such as leptin and adiponectin. Breast carcinomas need new blood vessels to maintain growth, ensure cell proliferation and fuel metastatic dissemination: vascular endothelial growth factor (VEGF) represents the most important pro-angiogenic factor, released by multiple TME components. The complement, a crucial part of the innate immune system, has emerged as a major regulator of cancer immunity. Complement anaphylatoxins in the TME can exert a pro- and anti-tumorigenic potential.

Fig. 3

Core biopsies of relapsed invasive breast carcinomas of no special type (NST) of triple-negative phenotype (a, b) assessed for PD-L1 expression by the SP142 assay (b, d): note in both cases the typical punctuate dark brown staining of immune cells.