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

SIMPLE SUMMARY: Intra-and inter-tumor heterogeneity characterizes breast cancer disease not only in terms of intrinsic cancer cell features, but also of its surrounding microenvironment that can be characterized by different stromal and immune cell types. Nonetheless, triple-negative breast cancers and HER2+ tumors are considered, among breast cancer molecular subtypes, the most immune infiltrated, and the level of TILs generally indicates a good prognosis. It is now clear that both cancer cell molecular heterogeneity and heterogeneity of the tumor microenvironment contribute to modulating the response to anti-HER2 agents. Uncovering all these levels of complexity will be a critical step in the design of patient-tailored treatments; additionally, recent technological advances in the analysis of tumor tissues, such as ssRNAseq and digital pathology, will be key in this process. ABSTRACT: 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.