Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine ...IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.
Hodgkin lymphoma (HL) is composed of two distinct pathological entities, nodular lymphocyte predominant HL and classic HL, the latter with four subtypes. In contrast with most other human lymphomas, ...in which the neoplastic cells are a major population of the tumour constituents, the neoplastic ‘Hodgkin (H) and Reed–Sternberg (RS)’ cells usually account for less than 10% of tumour bulk against an inflammatory background. The neoplastic cells of HL are of B-cell lineage (PAX5+) in virtually all cases. HL usually affects young patients with a localised nodal disease and its clinical behaviour is typically indolent. Patients respond well to chemotherapy with cure rates of 80–90% and the recent finding of PD-L1 expression, an immune checkpoint, warrants the use of immunotherapy for some patients with recurrent and/or refractory HL.
The enigmatic RS cells of HL are unique in their abundant cytoplasm and characteristic bilobed nuclei with eosinophilic prominent nucleoli, imparting an ‘owl-eye’ appearance. H cells are mononuclear variants. The viral inclusion-like morphology was a clue on the way to discovering an association between classic HL and Epstein–Barr virus (EBV). However, this association is variable in different geographic regions and in pathological subtypes, and correlates with older age (>60 years) and socioeconomic status, indicating that environmental factors are likely involved in HL pathogenesis. Virus-associated endoplasmic reticulum (ER) stress also may contribute to mechanisms underlying the characteristic morphological features of HRS cells. ER stress has been found to induce aberrant, cytoplasmic cyclin A expression, leading to nuclear hyperdiploidy. Aberrant expression of cyclin A is commonly associated with HRS cell morphology in HL, probably through EBV-latent membrane protein-1 (LMP1) signalling. Shelterin also may play a role in the morphogenesis of multinucleated RS cells. In addition, EBV-positive and -negative HL cases express survival, but not death signals of ER stress at similar levels and EBV-LMP1 transfection increases expression of survival signals in HL cell lines. These data suggest that surviving ER stress may be involved in HL pathogenesis.
Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed‐Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are ...infected by Epstein‐Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV‐latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV‐LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation‐induced autophagic stress, and alleviated autophagy inhibition‐ or doxorubicin‐induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte‐predominant and lymphocyte‐rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1‐positive HL xenografts with better efficacy than LMP1‐negative HL xenografts. Collectively, these results suggest that EBV‐LMP1 enhances autophagy and promotes the viability of HL cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with HL, especially EBV‐positive cases.
EBV‐LMP1 enhances autophagy and promotes viability of Hodgkin lymphoma cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with Hodgkin lymphoma, especially EBV‐positive cases.
Prostate cancer (PCa) is a leading cause of mortality and morbidity in men worldwide, and emerging evidence suggests that the CD44(high) prostate tumor-initiating cells (TICs) are associated with its ...poor prognosis. Although microRNAs are frequently dysregulated in human cancers, the influence of microRNAs on PCa malignancy and whether targeting TIC-associated microRNAs inhibit PCa progression remain unclear. In this study, we found that miR-320 is significantly downregulated in PCa. Overexpression of miR-320 in PCa cells decreases PCa tumorigenesis in vitro and in vivo. Global gene expression profiling of miR-320-overexpressing PCa cells reveals that downstream target genes of Wnt/β-catenin pathway and cancer stem cell markers are significantly decreased. MicroRNA-320 inhibits β-catenin expression by targeting the 3'-untranslated region of β-catenin mRNA. The reduction of miR-320 associated with increased β-catenin was also found in CD44(high) subpopulation of prostate cancer cells and clinical PCa specimens. Interestingly, knockdown of miR-320 significantly increases the cancer stem-like properties, such as tumorsphere formation, chemoresistance and tumorigenic abilities, although enriching the population of stem-like TICs among PCa cells. Furthermore, increased miR-320 expression in prostate stem-like TICs significantly suppresses stem cell-like properties of PCa cells. These results support that miR-320 is a key negative regulator in prostate TICs, and suggest developing miR-320 as a novel therapeutic agent may offer benefits for PCa treatment.
Correspondence to Professor Kung-Chao Chang, Pathology, National Cheng Kung University Hospital, Tainan 70428, Taiwan; changkc@mail.ncku.edu.tw Clinical question An 8-year-old boy, without underlying ...disease, presented to the otolaryngologist with sleep apnoea and snoring. An initial impression of paediatric-type follicular lymphoma was considered but the strong expression of MUM1/IRF4 suggests the alternative entity ─ follicular form of large B-cell lymphoma with IRF4 rearrangement.1 We, thus, performed a detailed fluorescence in situ hybridisation study using three-colour probes of mixed 6p25.3 region (IRF4) dual colour split probe and IGH 3’ probe (online supplementary figure S2). BCL2 protein is negative and BCL2 translocation is absent.2 Instead, there are frequent MAP2K1 mutations with MAPK/ERK pathway activation.3 Conventional FL, a rare lymphoid malignancy in paediatric patients, is composed of centrocytes and centroblasts.2 In contrary to paediatric-type FL, BCL2 protein is usually expressed, and BCL2 gene is rearranged.2 Finally, CD10-MUM1+FL, a variant of conventional FL, frequently affects the elderly, shows high-grade morphology often with diffuse proliferation and lacks BCL2/IGH translocation.4 The majority of cases carries BCL6 mutations and has a poorer prognosis.4 Initially lumped together with paediatric-type FL, large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) has been currently identified as a distinct entity by the WHO lymphoma classification.1 In 2011, Salaverria et al identified IRF4 breaks in a subgroup of diffuse large B-cell lymphoma or grade 3 FL.5 Most of the cases had an IG-IRF4 fusion and showed strong expression of IRF4/MUM1, distinct from conventional FL.
A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous ...lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T‐cell lymphoma, 92 (41.7%) cases, followed by CD30‐positive T‐cell lymphoproliferative disorders including lymphomatoid papulosis (n = 33, 14.9%) and cutaneous anaplastic large cell lymphoma (n = 12, 5.4%). The most frequent primary B‐cell lymphomas were marginal zone lymphoma (n = 8, 3.6%) and diffuse large B‐cell lymphoma (DLBCL), leg type (n = 8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low‐stage (T‐cell, 86%; B‐cell, 75%), whereas the majority of secondary lymphomas presented at high‐stage (T‐cell, 94%; B‐cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.
Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children and is frequently associated with Epstein-Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders ...(HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with papulovesicules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory agents is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.
Cancer cells can evade immune elimination by activating immunosuppressive signaling pathways in the tumor microenvironment (TME). Targeting immunosuppressive signaling pathways to promote antitumor ...immunity has become an attractive strategy for cancer therapy. Aurora-A is a well-known oncoprotein that plays a critical role in tumor progression, and its inhibition is considered a promising strategy for treating cancers. However, targeting Aurora-A has not yet got a breakthrough in clinical trials. Recent reports have indicated that inhibition of oncoproteins may reduce antitumor immunity, but the role of tumor-intrinsic Aurora-A in regulating antitumor immunity remains unclear. In this study, we demonstrated that in tumors with high lymphocyte infiltration (hot tumors), higher tumor-intrinsic Aurora-A expression is associated with a better prognosis in CRC patients. Mechanically, tumor-intrinsic Aurora-A promotes the cytotoxic activity of CD8
T cells in immune hot CRC via negatively regulating interleukin-16 (IL-16), and the upregulation of IL-16 may impair the therapeutic effect of Aurora-A inhibition. Consequently, combination treatment with IL-16 neutralization improves the therapeutic response to Aurora-A inhibitors in immune hot CRC tumors. Our study provides evidence that tumor-intrinsic Aurora-A contributes to anti-tumor immunity depending on the status of lymphocyte infiltration, highlighting the importance of considering this aspect in cancer therapy targeting Aurora-A. Importantly, our results suggest that combining Aurora-A inhibitors with IL-16-neutralizing antibodies may represent a novel and effective approach for cancer therapy, particularly in tumors with high levels of lymphocyte infiltration.
PDF
