Abstract
Simple SummaryImmunotherapy is a rapidly advancing field in breast cancer treatment, however, it encounters many obstacles that leave open gateways for breast cancer cells to resist novel immunotherapies. It is believed that the tumor microenvironment consisting of cancer, stromal, and immune cells as well as a plethora of tumor-promoting soluble factors, is responsible for the failure of therapeutic strategies in cancer, including breast tumors. Therefore, an in-depth understanding of key barriers to effective immunotherapy, focusing the research efforts on harnessing the power of the immune system, and thus, developing new strategies to overcome the resistance may contribute significantly to increase breast cancer patient survival. In this review, we discuss the latest reports regarding the strategies rendering the immunosuppressive tumor microenvironment more sensitive to immunotherapy in breast cancers, HER2-positive and triple-negative types of breast cancer, which are attractive from an immunotherapeutic point of view.Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.
Highlights
Recent reports of the International Agency for Research on Cancer indicate that breast cancer is the most frequent malignancy diagnosed worldwide with an estimated 2.3 million new cases and nearly 700,000 deaths in 2020 [1]
Due to the highly heterogeneous nature of breast cancer, it is difficult to select the one, relevant treatment option which will be precisely tailored for the patient
Some breast cancer patients benefit from therapies currently in use, still a large group do not respond to treatment or acquire resistance to them
Summary
Recent reports of the International Agency for Research on Cancer indicate that breast cancer is the most frequent malignancy diagnosed worldwide with an estimated 2.3 million new cases and nearly 700,000 deaths in 2020 [1]. Cancer immunotherapy has recently emerged as a forefront antitumor strategy It can be divided into three branches: passive immunotherapy (e.g., trastuzumab), active immunotherapy (e.g., checkpoint inhibitors), and adoptive immunotherapy (e.g., CAR-T cells). Targeting the biomarkers unique for the tumor cells or the immune checkpoints along with their ligands has revolutionized cancer immunotherapy. We discuss the landscape of immune system elements in breast cancer, mechanisms adopted by breast tumor cells to escape immunosurveillance, and the most recent immunotherapeutic approaches for BC patients. The crosstalk between cancer cells termed thethe imimmune landscape, plays a crucial role in tumor development and progression. Promotion of immune response, facilitating cancer cell disruption. Inhibition of immune response, promotion of tumor vascularization, effector cell cytotoxicity impairment, disruption of metabolism, and modulation of antigen-presenting cells (CD56bright CD16+ ). Inactivation of T cells and NK cells, ECM degradation, promotion of angiogenesis, inhibition of T cell proliferation and induction of T cell apoptosis, attracting immunosuppressive cells
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