Immune Escape during Breast Tumor Progression

Abstract

Immunotherapy using checkpoint inhibitors is one of the most promising current cancer treatment strategies. However, in breast cancer, its success has been limited to a subset of patients with triple-negative disease, whose durability of observed responses remain unclear. The lack of detailed understanding of breast tumor immune evasion mechanisms and the treatment of patients with highly heterogeneous metastatic disease contribute to these disappointing results. Here we discuss the current knowledge about immune-related changes during breast tumor progression, with special emphasis on the in situ-to-invasive breast carcinoma transition that may represent a key step of immunoediting in breast cancer. Comprehensive characterization of early-stage disease and better understanding of immunologic drivers of disease progression will likely expand the tools available for immunotherapy and improve patient stratification.

Figure 1.. Breast tumor progression in the context of immunoediting.

A) Breast tumor progression (top panel) is accompanied by numerous stromal modifications, particularly immunoediting (bottom panel). Normal milk ducts lined by luminal epithelial cells, myoepithelial cells, and basement membrane, progress to atypical hyperplasia through aberrant epithelial proliferation initiated by genetic and/or epigenetic alterations. Further acquisition of hereditary changes in combination with selection (I) promotes progression to ductal carcinoma in situ (DCIS), which is accompanied by an exclusion of leukocytes from the ducts (IV), recruitment and activation of surrounding immune infiltrates such as cytotoxic CD8⁺ T cells (IV), and extensive stromal reprogramming (I). The transition from DCIS to invasive ductal carcinoma (IDC) represents an evolutionary bottleneck, which associates with lack of myoepithelium and basement membrane (II) as well as further stromal alterations (II); see B and C for more detail. Only clones capable of immune evasion and survival in the stromal microenvironment persist. Immune escape might occur through various mechanisms before or during the DCIS-to-IDC transition (V), including downregulation of cancer neoantigens or MHCI/II genes, aberrant polarization of immune cells, recruitment of immune suppressive cells, and reduced cytotoxic immune responses. Distant metastasis, arising from single or multiple dissemination events (III), is characterized by an even more suppressive immune environment than IDC. B) Innate and adaptive immune responses can eliminate malignant cells. Antigen-presenting cells, including macrophages, prime lymphocytes such as CD8⁺ and CD4⁺ helper T (Th) cells and induce their clonal expansion. M1-activated macrophages also engulf and destroy cancer cells. Activated CD8⁺ T cells bind cognate neoantigens presented on MHC I/II via T-cell receptors (TCRs) and secrete cytotoxic granules. Th1 cells aid in CD8⁺ T-cell activation and differentiation of B cells into neoantigen-targeted antibody-producing plasma cells. NK-cell cytotoxicity is activated by the NK-cell receptor in an antigen-independent manner, but can also be triggered by antibody binding via CD16. C) Immune-escaper clones interact with stromal cells such as cancer-associated fibroblasts (CAFs) to secrete/induce secretion of immuno-modulatory cytokines that polarize immune responses. This results in a shift from immune-reactive to immune-suppressive microenvironments, marked by recruitment and polarization of tumor-associated macrophages (TAMs), Th2 polarization, and recruitment of Tregs and myeloid-derived suppressor cells (MDSCs). TAMs, MDSCs, Th2, and Treg cells inhibit the cytotoxic immune response, while CAFs also promote exclusion of CD8⁺ T cells from tumors. Tumor cells downregulate neoantigens and the antigen-presentation machinery and upregulate immune checkpoint proteins including PD-L1, which promotes exhaustion of CD8⁺ T cells through the PD-1 receptor. This immune-suppressive environment ultimately promotes tumor progression and metastasis.