Immunology and immunotherapy in breast cancer (original) (raw)
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Clinical advances in hematology & oncology : H&O, 2016
Immunotherapy encompasses both vaccines that direct immune responses to tumor-associated antigens, and checkpoint blocking antibodies that inhibit immune system suppression by targeting key pathways mediated by cytotoxic T-lymphocyte-associated antigen 4, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1). Both of these approaches currently are being explored as potential strategies for the treatment of breast cancer. Recent studies suggest that immunotherapy is poised to change the therapeutic landscape for some breast cancers. Specifically, overall response rates of 19% with PD-1/PD-L1-directed antibodies have been reported in 2 small studies of women with PD-L1-positive, heavily pretreated advanced triple-negative breast cancer. In combination with nab-paclitaxel, confirmed response rates were 46% in a PD-L1-unselected population in the first-line metastatic triple-negative breast cancer setting. Checkpoint-blocking antibodies also have been evaluated in small studi...
Oncology Research
Immunotherapy becomes a promising line of treatment for breast cancer (BC) however, its success rate is still limited. Methods: The study was designed to optimize the condition for producing an effective dendritic cell (DCs) based immunotherapy by using DCs and T lymphocytes together with tumor-infiltrating lymphocytes (TILs) and tumorinfiltrating DCs (TIDCs), treated with anti-PD1 and anti-CTLA4 monoclonal antibodies. This mixture of immune cells was co-cultured with autologous breast cancer cells (BCCs) isolated from 26 BC females. Results: There was a significant upregulation of CD86 and CD83 on DCs (p = 0.001 and 0.017, respectively), similarly upregulation of CD8, CD4 and CD103 on T cells (p = 0.031, 0.027, and 0.011, respectively). While there was a significant downregulation of FOXP3 and combined CD25.CD8 expression on regulatory T cells (p = 0.014 for both). Increased CD8/Foxp3 ratio (p < 0.001) was also observed. CD133, CD34 and CD44 were downregulated on BCCs (p = 0.01, 0.021, and 0.015, respectively). There was a significant increase in interferon-γ (IFN-γ, p < 0.001), lactate dehydrogenase (LDH, p = 0.02), and a significant decrease in vascular endothelial growth factor (VEGF, p < 0.001) protein levels. Gene expression of FOXP3 and Programmed cell death ligand 1 (PDL-1) were downregulated in BCCs (p < 0.001, for both), similarly cytotoxic T lymphocyte antigen-4 (CTLA4, p = 0.02), Programmed cell death 1 (PD-1, p < 0.001) and FOXP3 (p < 0.001) were significantly downregulated in T cells. Conclusion: Ex-vivo activation of immune cells (DCs, T cells, TIDCs, and TILs) with immune checkpoint inhibitors could produce a potent and effective BC immunotherapy. However, these data should be validated on an experimental animal model to be transferred to the clinical setting.
An overview of immune checkpoint inhibitors in breast cancer
Exploration of Targeted Anti-tumor Therapy
Although breast cancer is not traditionally considered an immunogenic type of tumor, the combination of immunotherapy and chemotherapy has recently emerged as a novel treatment option in triple-negative subtype in the advanced setting and other similar combinations of immune checkpoint inhibitors with chemotherapy are expected to become part of the neoadjuvant management in the near future. In addition, encouraging results have been observed with the combination of immune checkpoint blockade with diverse biological agents, including anti-HER2 agents, CDK 4/6 inhibitors, PARP-inhibitors. The present review summarized the available evidence coming from clinical trials on the role of immune checkpoint inhibitors in the management of breast cancer, both in advanced and early setting.
Targeted immunotherapy with a checkpoint inhibitor in combination with chemotherapy: A new clinical paradigm in the treatment of triple-negative breast cancer, 2019
Recent advances in the development of cancer immunotherapy using immune checkpoint inhibitors against either programmed death receptor-1 (PD-1) or its ligand PD-L1 have revolutionized treatment of several solid tumors [1-4]. The interaction between PD-1 on T-cells and its ligands PD-L1 and PD-L2 on cancer cells promotes T-cell exhaustion and conversion of T effector cells to immunosuppressive T regulatory (Treg) cells (Figure 1) [5]. Immune checkpoint inhibitors (against either PD-1 or PD-L1) block the suppressor PD-1/PD-L1 axis contributing to the reactivation of cytotoxic T effector cells and consequently enhancing the anticancer activity of the immune system (Figure 1) [5]. Stunning successes of monoclonal antibody-based immune checkpoint inhibitors against PD-1/PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab) have been achieved in various cancers [6]. These include non-small cell lung carcinoma (NSCLC), renal, bladder, head and neck, gastric/gastroesophageal junction (GEJ), microsatellite instable (MSI-H) colorectal, cervical, hepatocellular and Merkel cell carcinoma, as well as in malignant melanoma (both pediatric and adult) and classical Hodgkin' s lymphoma [6,7]. In addition, an anti-PD-1 agent pembrolizumab has been approved for all solid MSI-H cancers regardless the histotype ("tumor agnostic approach") [7-10]. Triple-negative breast cancer (TNBC) is a complex and highly aggressive subtype of breast cancer lacking estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2) receptors, thereby making it difficult to treat [11]. It carries the highest metastatic potential and has the poorest clinical outcome among all the subtypes of breast cancer [11]. Due to the advances in molecular characterization of TNBC, various novel therapeutic targets including poly ADP-ribose polymerase-1 (PARP-1) inhibitors, tyrosine kinase inhibitors, immune checkpoints, anti-androgens, and epigenetic targets have come into focus [11]. Although breast cancer has been initially considered a "non-immunogenic" cancer, numerous studies have now shown PD-L1 expression in both cancer and inflammatory cells (tumor infiltrating lymphocytes [TILs]). PD-L1 positivity in cancer or inflammatory cells has been reported across the breast cancer histotypes [12-26]. In particular, ER-negative breast cancers (TNBC and HER2 positive) have been shown to be "immunogenic" and potentially amenable for the trials
Checkpoint Inhibitors and Their Application in Breast Cancer
Breast Care, 2016
Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently ...
Acta Facultatis Medicae Naissensis, 2016
SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. ...
Immune checkpoints in aggressive breast cancer subtypes
Neoplasma, 2016
Immune checkpoints are molecules referred to inhibitory pathways in the immune system that play a pivotal role in prevention of autoimmunity and oncogenesis. The aim of the study was to evaluate expression levels of selected immune checkpoints-PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death 1 ligand 1) in breast cancer patients, suitable for breast conservation and sentinel node biopsy and determine their associations with clinicopathological factors. Expression of the genes coding for PD-1 and PD-L1 was analyzed in formalin-fixed paraffin-embedded specimens using realtime PCR. mRNA expression levels were determined using beta actin (ACTB) as an endogenous control. There was a trend towards significance between higher PD-1 and PD-L1 levels in triple negative breast cancers (p=0.1). Higher PD-L1 expression was also found in aggressive breast cancer subtypes e.g. triple negative and HER2 (human epidermal growth factor receptor 2)-positive as compared with subtypes with better prognosis such as luminal A and luminal BHER2-negative (p=0.05). There was a trend towards significance in higher PD-1 levels in triple negative and HER-2 positive breast cancers (p=0.1). A statistically significant difference was found between PD-L1 expression and tumor grade (p=0.01). Elevated PD-L1 levels were noted in G3 tumors. Immunogenicity appears to be gaining importance in triple negative and HER2-positive molecular subtypes of breast cancer, and the results in this study provide a basis for further investigation into the role of immune checkpoints in breast cancer.
Frontiers in immunology, 2017
There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC), particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes. Flow cytometric analysis of fresh tissue homogenates from untreated primary tumors show that PD-1 is principally expressed on CD4+ or CD8+ T cells and CTLA-4 is expressed on CD4+ T cells. The global proportion of PD-L1+, PD-L2+, LAG3+, and TIM3+ tumor-infiltrating lymphocytes (TIL) was low and detectable in only a small number of tumors. Immunohistochemically staining fixed tissues from the same tumors was employed to score TIL and tertiary lymphoid st...
Neoplasma, 2021
Immune checkpoint receptors (ICRs) were recently found to modulate the anti-tumoral immune response. This study aimed to determine the clinical and pathological associations of ICRs expression on tumor-infiltrating lymphocytes (TILs) in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy (NAC). Expressions of ICRs including PD-1, LAG-3, TIM-3, TIGIT, and CTLA-4 on CD8 + T lymphocytes and Natural Killer (NK) cells on TILs were analyzed by flow cytometry. Patients <50 years were more likely to express CTLA-4 on CD8 + T lymphocytes compared to those ≥50 years (p=0.004). In addition, patients with ypT3-4 tumors were more likely to have increased LAG-3 expression on CD16-CD56 bright NK cells (p=0.042) and PD-1 (p=0.014) and CTLA-4 (p=0.018) expressions on CD8 + T cells in regard to those with ypT1-T2, respectively. Contrarily, PD-1 expression on CD16-CD56 bright NK cells was found to be decreased in patients with ypN+ compared to those with ypN-(p=0.022). Furthermore, patients with HER2+ tumors were more likely to have increased TIM-3 expression on CD8+ T cells (p=0.043), whereas patients with a better response to NAC were more likely to express TIGIT on CD8 + T (p=0.014) and CD16-CD56 bright NK cells (p=0.003), respectively. The new generation ICRs, TIM-3, LAG-3, and TIGIT are highly expressed in LABC following NAC in patients with poor prognostic factors. Therefore, new evolving therapies using inhibitory mAbs directed to TIM-3, LAG-3, and TIGIT could be also be considered in locally advanced breast cancers expressing these ICRs.