The immune system and cancer evasion strategies: therapeutic concepts.

The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid-binding immunoglobulin-like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T-cell transfer.

Identification and translational validation of novel mammaglobin-A CD8 T cell epitopes.

Mammaglobin-A (MAM-A) is a secretory protein that is overexpressed in 80 % of human breast cancers. Its near-universal expression in breast cancer as well as its exquisite tissue specificity makes it an attractive target for a breast cancer prevention vaccine, and we recently initiated a phase 1 clinical trial of a MAM-A DNA vaccine. Previously, we have identified multiple MAM-A CD8 T cell epitopes using a reverse immunology candidate epitope approach based on predicted binding, but to date no attempt has been made to identify epitopes using an unbiased approach. In this study, we used human T cells primed in vitro with autologous dendritic cells expressing MAM-A to systematically identify MAM-A CD8 T cell epitopes. Using this unbiased approach, we identified three novel HLA-A2-restricted MAM-A epitopes. CD8 T cells specific for these epitopes are able to recognize and lyse human breast cancer cells in a MAM-A-specific, HLA-A2-dependent fashion. HLA-A2(+)/MAM-A(+) breast cancer patients have an increased prevalence of CD8 T cells specific for these novel MAM-A epitopes, and vaccination with a MAM-A DNA vaccine significantly increases the number of these CD8 T cells. The identification and translational validation of novel MAM-A epitopes has important implications for the ongoing clinical development of vaccine strategies targeting MAM-A. The novel MAM-A epitopes represent attractive targets for epitope-based vaccination strategies, and can also be used to monitor immune responses. Taken together these studies provide additional support for MAM-A as an important therapeutic target for the prevention and treatment of breast cancer.

Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer.

Recent studies in multiple epithelial cancers have shown that the inhibitory receptor programmed cell death 1 (PD-1) is expressed on tumor-infiltrating lymphocytes and/or programmed death ligand 1 (PD-L1) is expressed on tumor cells, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway. In addition, phase 1 clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 have shown promising results in several human cancers. The purpose of this study was to investigate the impact of PD-L1 expression in human breast cancer specimens. We conducted an immunohistochemistry study using a tissue microarray encompassing 650 evaluable formalin-fixed breast cancer cases with detailed clinical annotation and outcomes data. PD-L1 was expressed in 152 (23.4 %) of the 650 breast cancer specimens. Expression was significantly associated with age, tumor size, AJCC primary tumor classification, tumor grade, lymph node status, absence of ER expression, and high Ki-67 expression. In univariate analysis, PD-L1 expression was associated with a significantly worse OS. In multivariate analysis, PD-L1 expression remained an independent negative prognostic factor for OS. In subset analyses, expression of PD-L1 was associated with significantly worse OS in the luminal B HER2(-) subtype, the luminal B HER2(+) subtype, the HER2 subtype, and the basal-like subtype. This is the first study to demonstrate that PD-L1 expression is an independent negative prognostic factor in human breast cancer. This finding has important implications for the application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.

Nuclear expression of snail is an independent negative prognostic factor in human breast cancer.

BACKGROUND: Snail is a key regulator of epithelial-mesenchymal transition of tumor cells. Several studies have shown nuclear Snail expression to be a negative prognostic factor in human cancer, where it is generally associated with more aggressive tumor behavior and worse survival. OBJECTIVES AND METHODS: To further explore the role of Snail expression in breast cancer, we conducted a study on a tissue microarray, encompassing 1043 breast cancer cases. RESULTS: A total of 265 (25.4%) breast cancers were positive for Snail. Snail expression was significantly associated with greater tumor size, higher tumor stage and grade, positive lymph node status, and hormone receptor negative status and was differently expressed in the intrinsic subtypes of breast cancer, being the highest in the basal-like subtype and the lowest in the luminal A subtype. In multivariate analysis, Snail proved to be an independent negative prognostic factor for OS. In the intrinsic subtypes, Snail expression was a negative prognostic factor for OS in the luminal B HER2(-), the luminal B HER2(+), and the basal-like subtype. CONCLUSIONS: This is the first study demonstrating that nuclear Snail expression is an independent negative predictor of prognosis in breast cancer, thus suggesting that it may represent a potential therapeutic target.

The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer.

Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1(+) TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1(+) TIL were present in 104 (15.8 %) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1(+) TIL was associated with a significantly worse overall survival (HR = 2.736, p < 0.001). In subset analyses, the presence of PD-1(+) TIL was associated with significantly worse overall survival in the luminal B HER2(-) subtype (HR = 2.678, p < 0.001), the luminal B HER2(+) subtype (HR = 3.689, p < 0.001), and the basal-like subtype (HR = 3.140, p < 0.001). This is the first study to demonstrate that the presence of PD-1(+) TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.

EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer.

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is frequently expressed in breast cancer, and its expression has been associated with poor prognosis. Breast cancer can be subdivided into intrinsic subtypes, differing in prognosis and response to therapy. METHODS: To investigate the association between EpCAM expression and prognosis in the intrinsic subtypes of breast cancer, we performed immunohistochemical studies on a tissue microarray encompassing a total of 1365 breast cancers with detailed clinicopathological annotation and outcomes data. RESULTS: We observed EpCAM expression in 660 out of 1365 (48%) cases. EpCAM expression varied significantly in the different intrinsic subtypes. In univariate analyses of all cases, EpCAM expression was associated with a significantly worse overall survival. In the intrinsic subtypes, EpCAM expression was associated with an unfavourable prognosis in the basal-like and luminal B HER2(+) subtypes but associated with a favourable prognosis in the HER2 subtype. Consistently, specific ablation of EpCAM resulted in increased cell viability in the breast cancer cell line SKBR3 (ER(-), PR(-), and HER2(+)) but decreased viability in the breast cancer cell line MDA-MB-231 (ER(-), PR(-), and HER2(-) ). CONCLUSION: The differential association of EpCAM expression with prognosis in intrinsic subtypes has important implications for the development of EpCAM-targeted therapies in breast cancer.

PTP1B expression is an independent positive prognostic factor in human breast cancer.

Protein tyrosine phosphatase 1B (PTP1B) is a non-transmembrane protein tyrosine phosphatase that has come into focus as a critical regulator of multiple signaling pathways. The role of PTP1B in breast cancer remains unclear with evidence suggesting that PTP1B can exert both tumor-suppressing and tumor-promoting effects. To better define the role of PTP1B in human breast cancer, and its relationship with HER2, we performed immunohistochemical studies on a large cohort of functionally annotated primary breast cancer specimens. 683 of 1,402 (49 %) evaluable primary breast cancers are positive for PTP1B. There is no statistically significant association between PTP1B expression and age, tumor size, T stage, histologic grade, lymph node status, or histological subtype. Of note, there is no significant association between PTP1B expression and HER2 expression (PTP1B expression 53.1 % in HER2(+) cancers vs. 47.5 % in HER2(-) cancers, p = 0.0985). However, PTP1B expression is significantly associated with estrogen receptor expression (PTP1B expression 50.7 % in ER(+) cancers vs. 43.1 % in ER(-) cancers, p = 0.0137) and intrinsic molecular subtype (PTP1B expression 53.9 % in the luminal B HER2(+) subtype and 37.9 % in the basal-like subtype). Of note, multivariate analyses demonstrate that PTP1B is an independent predictor of improved survival in breast cancer (HR 0.779, p = 0.006). Taken together, we demonstrate in the largest study to date that (1) PTP1B is commonly expressed in breast cancer, (2) there is no association or functional impact of PTP1B expression in HER2(+) breast cancer, and (3) PTP1B expression in breast cancer is associated with significantly improved clinical outcome. Until additional studies are performed, caution should be exercised in using PTP1B inhibitors in human breast cancer.

[Embolization of hydrophilic guide wire coating]. / Embolisation von Katheterbeschichtung in das Myokard.

The number of interventional cardiovascular procedures has been rising steadily. Such procedures include the intravascular insertion of catheters and guide wires. These devices consist of a metallic core and coil that may be covered by hydrophilic coating to ease crossability and control for challenging lesions. We report two cases where insertion of a ChoICE® PT guide wire into the coronary artery led to embolization of the hydrophilic coating material with occlusion of small intramyocardial arteries.

[Ectomesenchymal chondromyxoid tumor of the anterior tongue]. / Ektomesenchymaler chondromyxoider Tumor des vorderen Zungenabschnitts.

Ectomesenchymal chondromyxoid tumor of the anterior tongue is a rare entity. To date, 37 cases have been reported in the literature. We present the case of a 52-year-old male patient with an ectomesenchymal chondromyxoid tumor at the typical location with a characteristic lobular proliferation of ovoid and fusiform uniform tumor cells on a chondromyxoid background and showing expression of typical immunohistochemical markers GFAP and S-100. Despite its rarity, this special tumor should be considered in the differential diagnosis when dealing with localized swellings of the anterior tongue.

Diagnostic and prognostic utility of PD-1 in B cell lymphomas.

AIMS: Programmed death-1 (PD-1) is expressed by germinal center-associated helper T-cells and acts as a negative regulator of the immune system. PD-1 is encountered on tumor cells of angioimmunoblastic T-cell lymphoma and is a postulated diagnostic marker in chronic lymphocytic leukemia (CLL/SLL). Recent data suggest prognostic importance of PD-1 in follicular lymphoma (FL). We assessed the diagnostic potential and the prognostic importance of PD-1 in B-cell lymphomas. METHODS: Distribution of PD-1+ lymphocytes in B-cell lymphomas was studied on 403 cases. Correlation with known biologic and clinical key data was performed. Prognostic cut-off scores were determined by receiver operating curve analysis. RESULTS: PD-1+ tumor-infiltrating lymphocytes were numerous in extranodal marginal zone lymphomas and FL. Their amount decreased from FL grade 1 to grade 3 and to FL with transformation to diffuse large B-cell lymphoma. An increased amount of PD-1 tumor-infiltrating lymphocytes above the prognostic cut-off score (> 2.8%) was a positive prognostic factor of disease-specific survival (DSS) in FL-patients. Five percent of the studied 66 CLL/SLL cases showed unequivocal PD-1 positivity of neoplastic cells. CONCLUSIONS: Increased number of PD-1+ tumor-infiltrating lymphocytes is associated with significantly improved DSS in FL and may be useful to predict its heterogeneous clinical behavior. PD-1 has probably limited diagnostic value for primary histopathological CLL/SLL diagnostics.