Impact of Immune Cell Heterogeneity on HER2+ Breast Cancer Prognosis and Response to Therapy

Breast cancer is a heterogeneous disease with a high degree of diversity among and within tumors, and in relation to its different tumor microenvironment. Compared to other oncotypes, such as melanoma or lung cancer, breast cancer is considered a "cold" tumor, characterized by low T lymphocyte infiltration and low tumor mutational burden. However, more recent evidence argues against this idea and indicates that, at least for specific molecular breast cancer subtypes, the immune infiltrate may be clinically relevant and heterogeneous, with significant variations in its stromal cell/protein composition across patients and tumor stages. High numbers of tumor-infiltrating T cells are most frequent in HER2-positive and basal-like molecular subtypes and are generally associated with a good prognosis and response to therapies. However, effector immune infiltrates show protective immunity in some cancers but not in others. This could depend on one or more immunosuppressive mechanisms acting alone or in concert. Some of them might include, in addition to immune cells, other tumor microenvironment determinants such as the extracellular matrix composition and stiffness as well as stromal cells, like fibroblasts and adipocytes, that may prevent cytotoxic T cells from infiltrating the tumor microenvironment or may inactivate their antitumor functions. This review will summarize the state of the different immune tumor microenvironment determinants affecting HER2+ breast tumor progression, their response to treatment, and how they are modified by different therapeutic approaches. Potential targets within the immune tumor microenvironment will also be discussed.