Immune microenvironment dynamics of HER2 overexpressing breast cancer under dual anti-HER2 blockade.

Introduction: The clinical prognosis of the HER2-overexpressing (HER2-OE) subtype of breast cancer (BC) is influenced by the immune infiltrate of the tumor. Specifically, monocytic cells, which are promoters of pro-tumoral immunosuppression, and NK cells, whose basal cytotoxic function may be enhanced with therapeutic antibodies. One of the standards of care for HER2+ BC patients includes the combination of the anti-HER2 antibodies trastuzumab and pertuzumab. This dual combination was a breakthrough against trastuzumab resistance; however, this regimen does not yield complete clinical benefit for a large fraction of patients. Further therapy refinement is still hampered by the lack of knowledge on the immune mechanism of action of this antibody-based dual HER2 blockade. Methods: To explore how the dual antibody challenge influences the phenotype and function of immune cells infiltrating the HER2-OE BC microenvironment, we developed in vitro 3D heterotypic cell models of this subtype. The models comprised aggregates of HER2+ BC cell lines and human peripheral blood mononuclear cells. Cells were co-encapsulated in a chemically inert alginate hydrogel and maintained in agitation-based culture system for up to 7 days. Results: The 3D models of the HER2-OE immune microenvironment retained original BC molecular features; the preservation of the NK cell compartment was achieved upon optimization of culture time and cytokine supplementation. Challenging the models with the standard-of-care combination of trastuzumab and pertuzumab resulted in enhanced immune cytotoxicity compared with trastuzumab alone. Features of the response to therapy within the immune tumor microenvironment were recapitulated, including induction of an immune effector state with NK cell activation, enhanced cell apoptosis and decline of immunosuppressive PD-L1+ immune cells. Conclusions: This work presents a unique human 3D model for the study of immune effects of anti-HER2 biologicals, which can be used to test novel therapy regimens and improve anti-tumor immune function.

The Peripheral Immune Landscape of Breast Cancer: Clinical Findings and In Vitro Models for Biomarker Discovery.

Breast cancer is the deadliest female malignancy worldwide and, while much is known about phenotype and function of infiltrating immune cells, the same attention has not been paid to the peripheral immune compartment of breast cancer patients. To obtain faster, cheaper, and more precise monitoring of patients' status, it is crucial to define and analyze circulating immune profiles. This review compiles and summarizes the disperse knowledge on the peripheral immune profile of breast cancer patients, how it departs from healthy individuals and how it changes with disease progression. We propose this data to be used as a starting point for validation of clinically relevant biomarkers of disease progression and therapy response, which warrants more thorough investigation in patient cohorts of specific breast cancer subtypes. Relevant clinical findings may also be explored experimentally using advanced 3D cellular models of human cancer-immune system interactions, which are under intensive development. We review the latest findings and discuss the strengths and limitations of such models, as well as the future perspectives. Together, the scientific advancement of peripheral biomarker discovery and cancer-immune crosstalk in breast cancer will be instrumental to uncover molecular mechanisms and putative biomarkers and drug targets in an all-human setting.