Fifty years ago, Burnet proposed the immune surveillance theory [1]. Immune surveillance is a process by which body can react to any transformed cells and destroy them before they multiplied and become tumors. Immune cells recognize transformed cells via new antigen which expressed on their surface and destroy them. Based on this theory the concept of immunotherapy for elimination of refractory tumors was gained interest [2]. However, outcome of clinical immunotherapies was not satisfying as expected. In past two decade, studies on understanding why certain cancers, mostly breast cancers harness immune recognition and elimination or evade body’s immune response, led to the concept of immunoediting which was proposed by Schreiber [3] to explain the immunodynamics between tumors and immune system. Immunoediting describes interactions between tumor cells and immunocytes in three phases: Elimination, Equilibrium, and Escape [4]. Immunoediting is characterized by changes in the immunogenicity of tumors due to the anti-tumor response of the immune system, resulting in the emergence of immune-resistant variants. During elimination phase of immunoediting process, effector immunocytes such as natural killer (NK) cells, with the help of dendritic cells and CD4+ T cells recognize tumor cells which poses relatively high immunogenicity and eliminate them before forming clinically significant mass. In contrast, tumor cells which are less immunogenic are able to escape elimination phase. Equilibrium phase is next step in cancer immunoediting, during which tumor cells that have escaped the elimination phase due to genetic and epigenetic changes to be resistance to immune system attack, become dormant as occult cancer cells and grow to emerge tumor mass which caught in the balance between anti-tumor and pro-tumor immunity in the tumor microenvironment. In the escape phase, tumor cells with poor immunogenicity continue to grow and expand in an uncontrolled manner and may eventually lead to malignancy [5].

Microscopic examination of these established malignant tumors, demonstrate presence of remarkable immune cells called tumor infiltrating lymphocytes (TILs). TILs are seen as a refection of tumor related immune response [6]. In spite of the fact TILs are present next to the tumor cells but can not destroy them. There is increasing evidence that biological vesicles such as exosomes secreted by tumor cells help to develop an immunosuppressive tumor microenvironment [7]. During the escape phase, tumor cell variant selected in the equilibrium phase have braked the host immune defenses with various mechanisms that lead to escape of cancer cells from effective immune response such as down regulation or loss of expression of major histocompatibility complex class I (HLA-A, B, C) which essential for effective cell mediated immune response development in tumor microenvironment [8]. This immunosuppressive effect works as a protective barrier to cancer cells [9]. Furthermore, escaped cancer cells are able to produce cytokines which can cause apoptosis of activated t cells [10]. Another mechanism of tumor cell evade immune response is upregulation of major histocompatibility complex class I (HLA-E, F, G) which inactivate NK cells [11] necessary for eliminating cancer cells. In addition, expression of immune checkpoints increased the frequency of immunosuppressive cells including regulatory T cells, myeloid-derived suppressor cells, immunomodulatory factors including tumor growth factor, and vascular endothelial growth factor in tumor microenvironment cause peripheral tolerance [12]. Tumors also can evade destruction by immune system expressing surface ligands (PD-L1) that engage with inhibitory receptors on the tumor- specific T cells (PD-1) in order to deactivate cytotoxicity function of T-cells and survive in the body. PD-1 is a member of immunoglobulin superfamily and acts to inhibit the immune response by inactivation of the T cells on which it is expressed. PD-1 is also expressed on B-cells, myeloid cells, and natural killer cells. PD-1 is activated by its ligand PD-L1 which is expressed on many immune cells as well as on some cancer cells [13].

Breast Cancer is the most common non-cutaneous cancer in women worldwide. This cancer affects 14% women and comprise more than 22% of invasive cancers in women and 16% all female cancers [14]. management of breast cancer depends on various factors including genetic background of patients, type of cancers which identified by tumor histological examination followed by immune-histochemistry (IHC) staining of patient’s biopsy, stage of the cancer, and patient’s age. Treatment is usually starting with surgical removal of the tumor and followed by chemotherapy and/or radiotherapy, and/or immunotherapy depending on aggressiveness of the tumor. In some cases, neoadjuvant therapy may be required prior to surgery and in case of advanced stage with risk of disease relapse, adjuvant therapy using hormone-blocking agents or chemotherapy or monoclonal antibodies may be necessary to prolong patient’s disease-free life [15].

In order to overcome limited efficacy of the immune response against tumor, concept of cancer immunotherapy gained attention. Using this type of therapy, immune system can be educating to recognize and attack specific cancer cells, boost immune cells activity to eliminate cancer cells, and provide the body with additional components to enhance the immune system. Adaptive immunotherapy was among the first regimens of immunotherapy used for treating solid tumor [16]. Adaptive immunotherapy means transfer of immune cells with anti-tumor activity into patient to attack tumor and kills cancer cells. This type of cancer treatment is gaining in popularity due to reports of success is increasing high specific activity with minimal toxicity side effects contributed to acceptance immunotherapy by clinicians as either single therapy or in combination with chemotherapies and/or radiotherapies. There are four major types of adaptive T cells transfer therapy which clinically being used: Epstein-Bar virus (EBV) specific T cells for EBV-associated malignancies; Tumor-infiltration lymphocytes (TIL) for metastatic malignancies and ovarian cancer; genetically modified T cells directed against various solid and hematological malignancies; natural killer (NK) cells as an immunotherapy [17]. Currently, many other types of cancer immunotherapies are applied:  immune checkpoint inhibitors therapy; tumor-infecting virus therapy; gene therapy; immunomodulator therapy; targeted antibody therapy; oncolytic virus therapy; biologic therapy. While all these immunotherapies showed promising for elimination of tumor cells in patients, it should be noted that the recent clinical success using checkpoint inhibition blockade and CAR T cell therapies has marked beginning of new era in cancer immunotherapy [18,19].  

Breast cancer is one of the most commonly studied tumors for the presence of immune system cells in the lesion and scores of ongoing clinical trials are evaluating the role of immunotherapy in breast cancer prevention and treatment [20]. The study of the immune microenvironment in breast cancer started with the identification od cancer associated antigen. One of the first breast cancer associated antigens identified was the glycosylation of MUC-1 [21]. It has been shown that breast cancer possesses type II immune microenvironment that supports the development of a primary antibody response, but not support the proliferation and maintenance of CD8+ cytotoxic T cells which is important immune cell for tumor elimination. An evaluation of cytokine release by antigen specific T cells directed against HER2, CEA, and MAGE3 demonstrated that breast cancer patients were lacking CD4+ T cells that were capable of secreting INF [22]. Additional investigations have shown that as breast cancer progresses, Type I immune responses that had developed against breast cancer antigen such as HER2 or HER3 began to diminish and eventually decrease to the point of no detection. Loss of immunity was associated with persistent disease after standard therapy [23]. Breast cancers that show a high degree of pre-existing immunity have been described as inflamed cancer types and are characterized by presence of high TIL cells population, program death ligand-1 (PDL-1) positivity of tumors or immune cells, high CD8+ T cells or presence of strong INF producing T cells [24]. Non-inflamed tumors are generally poorly infiltrated by TIL cells, exhibit low expression of PDL-1 and are characterized by low antigen presentation and are incapable of mounting an effective anti-tumor immune response [25]. Triple negative breast cancer (TNBC) and HER2 positive breast cancers are immunogenic as reflected by higher proportion of TIL cells compare to hormone-sensitive breast cancers which are considered non-inflamed tumors [26]. 

TNBC accounts for 15-20% of all breast carcinoma and associated with earlier age of onset, aggressive clinical course, and hopeless prognosis compared to HER2-positive breast carcinoma [27]; thus, most of the initial cancer immunotherapy have focused on TNBC. Given the lack of effective treatment in this type of breast cancer, several studies conducted in recent years to increase the therapeutic opportunity for TNBC patients [28]. It has been shown that chemotherapy with neoadjuvant increase TIL cells in tumor microenvironment with high number of CD8+ cytotoxic t cells or a high CD8+/FOXP3+ ratio which define TNBC patients with better prognosis following immune checkpoint inhibitors therapy [29]. The ability of immune system to detect and fight cancer cells is largely based on two key components: immune system has to recognize cancer cells as being different from normal cells meaning expression of neoantigens in cancer cells, and the second determinant of the immune response is the ability to change the number and function of immune cells when needed. One of the parameters in this context presence of great number of TILs in tumor microenvironment [30]. In breast cancer higher population of TILs is associated with aggressiveness of tumor type and also linked with improved outcome and response to chemotherapy and/or immunotherapy [31]. TILs also have been shown to be an independent prognostic marker in TNBC, whereas they are not predictive in ER-positive disease. It has also shown that TILs can be linked with an increased therapeutic response in HER2-positive breast cancer and TNBC [32].

Although immune checkpoint inhibitors [ICIs] therapy has demonstrated substantial single agent effectivity, it is only a relatively small subgroup of patients get benefit by this regimen therapy. For those breast cancer tumors subtypes which lack of great population of TIL cells in their microenvironment, it would be necessary to enhance immunogenicity of the breast cancer in order to increase population of TILs in the tumor for more effective ICIs. Many agents such as anthracyclines, platinum salts, taxanes, cyclophosphamide, and gemcitabine are a few agents that increase infiltration of immune cells into tumor microenvironment [33]. In addition, chemotherapy can induce multiple immunomodulatory changes in the tumor microenvironment, including increased antigen release by tumor cells, PDL-1 upregulation, and hyperexpression of immunogenic cell surface markers like MHC class I. It has been shown these modifications will positively influence the effectiveness of breast cancer immunotherapy [34].