The Immunology of Hormone Receptor Positive Breast Cancer.

Jonathan Goldberg,Janae Davis,Ricardo G Pastorello,Jennifer L Guerriero,Tuulia Vallius,Judith Agudo,Adrienne G Waks,Tanya Keenan,Yvonne Xiaoyong Cui,Elizabeth A Mittendorf,Sandra S Mcallister,Sara M Tolaney

doi:10.3389/fimmu.2021.674192

Abstract

Immune checkpoint blockade (ICB) has revolutionized the treatment of cancer patients. The main focus of ICB has been on reinvigorating the adaptive immune response, namely, activating cytotoxic T cells. ICB has demonstrated only modest benefit against advanced breast cancer, as breast tumors typically establish an immune suppressive tumor microenvironment (TME). Triple-negative breast cancer (TNBC) is associated with infiltration of tumor infiltrating lymphocytes (TILs) and patients with TNBC have shown clinical responses to ICB. In contrast, hormone receptor positive (HR+) breast cancer is characterized by low TIL infiltration and minimal response to ICB. Here we review how HR+ breast tumors establish a TME devoid of TILs, have low HLA class I expression, and recruit immune cells, other than T cells, which impact response to therapy. In addition, we review emerging technologies that have been employed to characterize components of the TME to reveal that tumor associated macrophages (TAMs) are abundant in HR+ cancer, are highly immune-suppressive, associated with tumor progression, chemotherapy and ICB-resistance, metastasis and poor survival. We reveal novel therapeutic targets and possible combinations with ICB to enhance anti-tumor immune responses, which may have great potential in HR+ breast cancer.

Highlights

Immunotherapy represents a paradigm shift in oncology
We recently reported that in HR+/human epidermal growth factor receptor 2 (HER2)- breast tumors analyzed before and after neoadjuvant chemotherapy (NAC), stromal TILs (sTILs) and CD8+ cells were significantly decreased after treatment, whereas expression analyses revealed that there was increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy
Several studies have demonstrated that high TILs and PD-L1 expression have been linked to predictive benefit of anti-programmed death1 (PD-1)/L1 therapy in Triple-negative breast cancer (TNBC) [16]

Summary

Introduction

Immunotherapy represents a paradigm shift in oncology. In particular, immune checkpoint blockade (ICB) has emerged as an efficacious treatment option for many tumor types, providing new therapeutic options for previously untreatable cancers. ICB therapy involves the use of humanized antibodies to target and neutralize immune checkpoint proteins with the goal of Immunology of HR+ Breast Cancer invigorating T cell activation and anti-tumor responses. Cancers that respond to ICB have at least one of these three key features: high tumor mutational burden (TMB), high numbers of tumorinfiltrating-lymphocytes (TILs) and/or high PD-L1 expression [2]. Tumors from melanoma and lung cancer patients generally exhibit all of these features and have demonstrated superior responses to ICB [3,4,5]. Breast tumors generally have low TMB, are often poorly infiltrated by TILs, have low levels of PD-L1 expression, and are considered to be nonimmunogenic and less responsive to ICB [6,7,8,9]

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Conclusion