PURPOSE: This study was designed to find a reliable Epstein-Barr virus (EBV) immunoglobulin (Ig) G-based diagnostic/screening test for nasopharyngeal carcinoma (NPC) able to demarcate between the NPC-related seropositivity of EBV IgG antibodies and that of other head and neck cancer (HNCA) and control groups. The NPC-associated immunosuppression affects EBV IgA much more than IgG, leading to inconsistent detection of NPC using EBV IgA antibodies.
MATERIALS AND METHODS: One hundred twenty-two HNCA patients, 42 NPC, 66 laryngeal carcinoma, and 14 hypopharyngeal carcinoma and 3 groups of 100 control subjects were enrolled in this study. Enzyme-linked immunosorbent assay (ELISA) was used to find a specific cutoff value for the NPC-related seropositivity of EBV IgG antibodies.
RESULTS: NPC group showed higher serum level of EBV IgG antibodies than control and other HNCA groups (P < .05). However, the traditional cutoff value, mean + 2 SDs of control subjects, failed to demarcate the seropositives of NPC patients from those of healthy population (P > .05). The new cutoff value, mean + 2 SDs of the seropositives group of control subjects who had already been grouped by the traditional cutoff value, proved successful. It succeeded to demarcate between the NPC-related EBV IgG seropositivity and that issued from the persistent, latent, or reactivated EBV infection in the population (P < .05). The sensitivity/specificity of NPC detection by the new cutoff-based ELISA kit, 76.19% and 86%, was close or higher than that of EBV IgA antibodies.
CONCLUSION: EBV IgG-based ELISA could be used for the diagnosis of NPC using a new cutoff threshold that excludes the population baseline of EBV IgG seropositivity.
Matched MeSH terms: Head and Neck Neoplasms/immunology; Hypopharyngeal Neoplasms/immunology; Laryngeal Neoplasms/immunology; Nasopharyngeal Neoplasms/immunology
Immunology is a discipline that traverses all branches of clinical medicine. Thus since about ten years ago major hospitals in Malaysia established routine clinical immunology services particularly in the diagnosis of autoimmune/connective tissue disorders. More recently these laboratories have ventured into basic research in Dengue Haemorrhagic Fever, Leukaemia Immunology, Nasopharyngeal Cancer and Leprosy. The rationale for these projects together with early results from them are discussed.
Hybridoma clone C3A8, which is a fusion product between splenic lymphocytes of Balb/c mice immunized with MCF7 breast carcinoma cells and SP2/0 myelomas, was produced and characterized. A stable clone that secreted IgM monoclonal antibody (MAb) with kappa light chain was obtained through limiting dilutions. Cell-ELISA screening, flow cytometry analysis, and immunofluorescence staining revealed that the MAb C3A8 had bound specifically and strongly to MCF7 and HT29 but cross reacted weakly or not on HeLa cell line. The MAb C3A8 reacted positively with paraffin-embedded tissues of human breast and colon cancers but there were no positive reactions on normal tissues. Western blot analysis showed the MAb recognized a 55 kDa protein, which was present in the extract of MCF7 and HT29 cell lines. Our results demonstrated that MAb C3A8 could be used for basic and clinical research of breast and colon cancers.
Matched MeSH terms: Breast Neoplasms/immunology*; Ovarian Neoplasms/immunology*
The BamHI Z EBV replication activator (ZEBRA) protein is involved in the switch from latency to productive cycle of Epstein-Barr virus. A recombinant ZEBRA protein was synthesized and assessed in enzyme-linked immunosorbent assay (ELISA) for serum IgG response in nasopharyngeal carcinoma (NPC) patients. In 100 NPC serum samples that were positive for IgA to the EBV viral capsid antigen (VCA), 75% had IgG anti-ZEBRA antibodies. In contrast, only 3/83 (3.6%) serum samples from healthy donors and 2/50 (4%) from other cancers were positive for IgG to ZEBRA. Interestingly, in a selected group of 100 NPC sera negative for IgA to VCA, 25% contained IgG anti-ZEBRA antibodies. This suggests that the ELISA for IgG anti-ZEBRA may also identify earlier cases of NPC not detected by the conventional immunofluorescence test for IgA to VCA.
Immunization with anti-idiotype (Id) antibodies represents a novel new approach to active immunotherapy. Extensive studies in animal tumor models have demonstrated the efficacy of anti-Id vaccines in preventing tumor growth and curing mice with established tumor. We have developed and characterized several murine monoclonal anti-Id antibodies (Ab2) which mimic distinct human tumor-associated antigens (TAA) and can be used as surrogate antigens for triggering active anti-tumor immunity in cancer patients. Encouraging results have been obtained in recent clinical trials. In this article, we will review the existing literature and summarize our own findings showing the potential of this approach for various human cancers. We will also discuss where anti-Id vaccines may perform better than traditional antigen vaccines.
Matched MeSH terms: Breast Neoplasms/immunology; Neoplasms/immunology*; Colorectal Neoplasms/immunology
One of the most common cancers worldwide is oral squamous cell carcinoma (OSCC), which is associated with a significant death rate and has been linked to several risk factors. Notably, failure to detect these neoplasms at an early stage represents a fundamental barrier to improving the survival and quality of life of OSCC patients. In the present study, serum samples from OSCC patients (n = 25) and healthy controls (n = 25) were subjected to two-dimensional gel electrophoresis (2-DE) and silver staining in order to identify biomarkers that might allow early diagnosis. In this regard, 2-DE spots corresponding to various up- and down-regulated proteins were sequenced via high-resolution MALDI-TOF mass spectrometry and analyzed using the MASCOT database. We identified the following differentially expressed host-specific proteins within sera from OSCC patients: leucine-rich α2-glycoprotein (LRG), alpha-1-B-glycoprotein (ABG), clusterin (CLU), PRO2044, haptoglobin (HAP), complement C3c (C3), proapolipoprotein A1 (proapo-A1), and retinol-binding protein 4 precursor (RBP4). Moreover, five non-host factors were detected, including bacterial antigens from Acinetobacter lwoffii, Burkholderia multivorans, Myxococcus xanthus, Laribacter hongkongensis, and Streptococcus salivarius. Subsequently, we analyzed the immunogenicity of these proteins using pooled sera from OSCC patients. In this regard, five of these candidate biomarkers were found to be immunoreactive: CLU, HAP, C3, proapo-A1 and RBP4. Taken together, our immunoproteomics approach has identified various serum biomarkers that could facilitate the development of early diagnostic tools for OSCC.
A phage display library of single chain variable fragment (scFv) against MCF-7 breast cancer cells was constructed from C3A8 hybridoma cells. RNA from the C3A8 was isolated, cDNA was constructed, and variable heavy and light immunoglobulin chain gene region were amplified using PCR. The variable heavy and light chain gene regions were combined with flexible linker, linked to a pCANTAB 5E phagemid vector and electrophoresed into supE strain of Escherichia coli TG1 cells. Forty-eight clones demonstrated positive binding activity to MCF-7 breast cancer cell membrane fragments and the strongest of 48 clones was selected for analysis. The anti-MCF-7 library evaluated by SfiI and NotI digests demonstrated that anti-MCF-7 scFv antibodies possess individual patterns that should be able to recognize distinct human breast cancer cells. The C3A8 scFv, with an apparent molecular weight of 32 kDa, showed high homology (99%) with single chain antibody against rice stripe virus protein P20. In summary, the anti MCF-7 scFv antibody can be used for pretargeting breast cancer for clinical diagnosis of patients; it also has potential for therapeutic applications.
Immune checkpoint inhibitors (ICIs) are revolutionizing the treatment of many cancers and have demonstrated their potential as 'cancer terminators'. However, ICI treatment also has constraints, such as its immune-related adverse events (irAEs) and therapeutic resistance. These drawbacks are gradually being overcome through better knowledge of the immune system, history of disease, duration of treatment, combinational drug regimes, adequate biomarkers, and effective patient response monitoring. In this review, we discuss the present ICI therapy landscape and its therapeutic outcomes for various diseases. We also highlight biomarkers related to the ICI response.
There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells.
Dendritic cells (DCs) are cells derived from the hematopoietic stem cells (HSCs) of the bone marrow and form a widely distributed cellular system throughout the body. They are the most efficient, potent, and professional antigen-presenting cells (APCs) of the immune system, inducing and dispersing a primary immune response by the activation of naïve T-cells, and playing an important role in the induction and maintenance of immune tolerance under homeostatic conditions. Thus, this review has elucidated the general aspects of DCs as well as the current dynamic perspectives and distribution of DCs in humans and in various species of animals that includes mouse, rat, birds, dog, cat, horse, cattle, sheep, pig, and non-human primates. Besides the role that DCs play in immune response, they also play a pathogenic role in many diseases, thus becoming a target in disease prevention and treatment. In addition, its roles in clinical immunology have also been addressed, which include its involvement in transplantation, autoimmune disease, viral infections, cancer, and as a vaccine target. Therefore, based on the current knowledge and understanding of the important roles they play, DCs can be used in the future as a powerful tool for manipulating the immune system.
Tumour-associated macrophage (TAM) serves as the site in which most inflammatory cells coreside. It plays an important role in determining the progression and metastasis of a tumour. The characteristic of TAM is largely dependent on the stimuli present in its tumour microenvironment (TME). Under this environment, however, M2 macrophages are found to be in abundance compared to M1 macrophages which later promote tumour progression. Numerous studies have elucidated the relationship between TAM and the progression of tumour; hence, TAM has now been the subject of interest among researchers for anticancer therapy. This review discusses the role of TAM in colorectal cancer (CRC) and some of the potential candidates that could reeducate TAM to fight against CRC. It is with hope that this review will serve as the foundation in understanding TAM in CRC and helping other researchers to select the most suitable candidate to reeducate TAM that could assist in enhancing the tumouricidal activity of M1 macrophage and eventually repress the development of CRC.
With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-β, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.
Nasopharyngeal carcinoma (NPC) and other head and neck cancer (HNCA) types show a great epidemiological variation in different regions of the world. NPC has multifactorial etiology and many interacting risk factors are involved in NPC development mainly Epstein Barr virus (EBV). There is a need to scrutinize the complicated network of risk factors affecting NPC and how far they are different from that of other HNCA types.
Complementary and alternative medicine (CAM) use is prevalent among individuals with cancer, especially breast cancer survivors. This study was conducted among 394 breast cancer survivors in selected regions of Peninsular Malaysia to identify the pattern and factors associated with CAM use. About 51% of the respondents reported CAM use as complementary treatment. Vitamins (47.2%), spiritual activities (33.2%) and other dietary supplements (30.7%) were the most commonly used CAM therapies. Common reasons for CAM use were to increase the body's ability to perform daily activities (70.9%), enhance immune function (58.3%) and improve emotional well-being (31.7%). Users obtained CAM information mainly from friends and family members (62.5%), physicians (25.0%) and mass media (13.9%). Ethnicity and years of education were significantly associated with CAM use. Although no adverse effects of CAM were reported, breast cancer survivors should discuss their CAM use with health professionals to prevent potential adverse effects of these therapies.
A 13 year old boy presented with a huge mass on his right arm of 6 months duration. Histopathological examination revealed sheets of malignant small round blue cells with immunopositivity for LCA, CD43, CD45Ro, CD30, EMA, ALK-1 and CD99, and negativity for CD20, TdT, myogenin, myoD1, NSE, bcl-6, bcl-2 and CD10. Fluorescent In-Situ Hybridization (FISH) testing excluded the diagnosis of Ewing's sarcoma/PNET. Pathologists need to be aware of the diagnosis of a small cell variant of ALCL, as well as of the fact that CD99 expression commonly occurs in cases of ALK-positive ALCL, in order to distinguish this entity from Ewing's sarcoma/PNET.
Autoantibodies to survivin have been reported in lung cancers and in gastrointestinal cancers. A few reports have also described a low prevalence of autoantibodies to survivin and at low titres in the sera of breast cancer patients with no implications for their clinical usefulness. This study was designed to re-examine the prevalence and the clinical correlations of autoantibodies to the tumour protein survivin, in the sera of patients with infiltrating ductal carcinoma of the breast using an ELISA assay. In spite of the low prevalence of autoantibodies to survivin (7%, n = 57), their presence was associated with grade III tumours, with tumour sizes exceeding 10cm, with axillary lymph nodal involvement and with metastases. Moreover, all the autoantibody-positive cases were estrogen and progesterone receptors negative. Furthermore, all the autoantibody-positive cases expressed survivin with high scores.
We conducted a prospective study of 60 patients in a tertiary care referral center to ascertain the status of cell-mediated immunity as determined by delayed hypersensitivity reactions in patients with nasopharyngeal carcinoma (NPC) or allergic rhinitis. Delayed hypersensitivity as detected by Mantoux testing is generally accepted as a reflection of the level of cell-mediated immunoactivity-the less hypersensitivity reaction that occurs, the lower the level of immunoactivity is, and vice versa. Our study population was made up of three groups: 20 newly diagnosed patients with NPC (pretreatment), 20 age- and sex-matched patients with allergic rhinitis, and 20 matched controls without either disease. A negative Mantoux test (0- to 5-mm induration) was seen in 13 patients with NPC (65.0%), in 17 patients with allergic rhinitis (85.0%), and in 16 controls (80.0%); none of these differences was statistically significant. However, it is interesting that while the NPC group had the lowest percentage of negative Mantoux results overall, it had the highest percentage of patients who had no reaction at all (i.e., 0-mm induration); a complete absence of any reaction was seen in 7 of the 13 Mantoux-negative NPC patients (53.8%), compared with 2 of the 17 Mantoux-negative allergic rhinitis patients (11.8%) and 3 of the 16 Mantoux-negative controls (18.8%). An absence of a reaction generally indicates a very limited degree of cell-mediated immunoactivity. Therefore, we conclude that patients with NPC appear to have significantly less cell-mediated immunity than do patients with allergic rhinitis and normal controls; no statistically significant difference was noted between the latter two groups.
Study site: ENT clinic, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia