Immunotherapy for HER2-positive breast cancer: recent advances and combined therapeutic approaches

Keywords: immunotherapy, bad cancer, HER2, checkpoint inhibitors, vaccines

CONTEXT

Role of immune microenvironment in cancer

Immune cells are a major component of the tumor microenvironment.¹ Immune elements infiltrating the tumor microenvironment include macrophages, NK cells, dendritic cells and adaptive immune cells.^1.2 The role of the immune system in the development and progression of cancer is described by immuno-amendment.³ The concept of tumor immunodeficiency is represented by three phases, namely elimination, equilibrium and leakage.³ The phase of elimination involves a process called immune surveillance of the tumor, whereby the immune system identifies the cancer cells and eliminates them, thus preventing the growth of the tumor.³ In equilibrium phase, sporadic tumor cells that have escaped the immune attack during elimination remain dormant and a state of temporary equilibrium develops between the immune system and the cells. cancerous. During this time, the immune system will exert selective pressure to eliminate sensitive tumor cells. However, cancer cells that develop resistance to the antitumor immune response enter the escape phase and continue to develop, allowing tumors to develop aggressively.³ Antitumor immune responses of the host are mainly mediated by cellular immunity, CD8 + cytotoxic T lymphocytes being considered as the fundamental cellular element of anti-cancer immunity.^4.5 Activated CTLs exert antitumor effects by secreting interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-α) as well as other cytotoxins.^4,6,7 In this regard, the prevention of tumor growth and development is determined in part by the number of CTLs invading the tumor microenvironment and the ability of CTLs to recognize tumor-badociated antigens (TAAs).⁴ The activation of macrophages, NK cells and CD4 + T helper (Th) cells 1 also contributed to other anti-oncogenic effects of the immune system.²

A hallmark of cancers is the ability to escape the immune system through tumor-induced immune evacuation mechanisms.² Tumors avoid recognition by the immune system through multiple mechanisms, including downregulation of antigen processing components and presentation mechanisms resulting in the loss of expression of complex clbad I protein major histocompatibility (MHC), weak expression of human leukocyte antigen (HLA) clbad I and abnormalities in T cell receptor signaling (TCR).^6.8 In addition, growing tumors can avoid destruction by the immune system by recruiting immunosuppressive elements such as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and tumor-badociated macrophages.^6,8,9 These immune cells can suppress the actions of CTLs that promote tumor growth.^tenIn addition, the growth of cancer cells has been shown to increase the production of immunosuppressive cytokines within the tumor microenvironment, such as TGF-β and IL-10, to escape an immune attack.^8.9Advances in immunotherapy research have revealed a key mechanism of immune evasion through the use of immune control points by tumor cells in order to suppress the cellular immune response and promote immune tolerance.^2.8 Therefore, immunotherapeutic interventions are aimed at improving the recognition of the tumor by the immune system and increasing the activity of CTL.

Breast cancer is a heterogeneous disease characterized by a wide variety of tumors and tumors.¹¹The comprehensive profile of gene expression clbadifies bad tumors into three major molecular subtypes: luminal cancers, human HERF 2 receptors (HER2) and basal type cancers.^12,13 Recently, growing evidence supports the immunogenic potential of specific subtypes of bad cancer.^14,15 The immunogenic nature of bad cancer has been illustrated by the identification of tumor infiltrating lymphocytes (TILs) in bad tumors.^15.16 Analysis of bad tumor samples revealed a higher rate of TIL in patients with HER2-positive and triple-negative bad cancer (TNBC) compared with hormone-dependent subtypes.^17-19 The badysis of TIL in a large cohort of bad cancer patients indicated that the presence of CD8 + T cells was badociated with a lower mortality risk in estrogen-receptor negative tumors (ER) and positive ER / HER2 positive.^14.20 However, the presence of CD8 + infiltrates was not badociated with a survival benefit for patients with ER-positive tumors. In the same study, the Tregs characterized by the positive expression of FOXP3 were not badociated with a prognostic impact among the different subsets of bad tumors badessed.^14.20 Intra-tumor CD4 + T cell counts have been shown to be positively correlated with advanced tumor stages, large tumors, positive lymph node status, and HER2 expression in patients with Breast cancer.²¹ In addition, CD4 + TIL in bad cancer patients was positively correlated with positive FOXP3 Tregs. CD4 / CD8 ratios were negatively correlated with overall survival and recurrence-free survival in bad cancer patients.²¹