Project description:Microarray gene expression of peripheral blood of the prostate cancer patients receiving localized external beam radiation therapy (EBRT) Assay processed at EBRT time points, baseline, midpoint (days 19-21) and endpoint (days 38-42)
Project description:The etiology behind cancer-related fatigue (CRF) is currently unknown. The physiological mechanisms of CRF are based on limited evidence that genetic factors, energy expenditure, metabolism, aerobic capacity, and the individual's immune response to inflammation are responsible for the experience of CRF. Gene expression profiling using microarray analysis from white blood cells of men with non-metastatic prostate cancer shows significant, differential expression of 463 probesets during localized external beam radiation therapy (EBRT). Pathway analysis shows a central role of SNCA (alpha-synuclein gene) among these differentially expressed probesets. Significant expression of SNCA was confirmed by qPCR (p<.001) and ELISA (p<.001) over time during EBRT. A significant correlation was noted between averaged fatigue scores and delta CT values of SNCA expression using confirmatory qPCR over time during EBRT (R=-.90, p=.006). Development of fatigue experienced by these men during EBRT may be mediated by SNCA expression. Pathways related to alpha-synuclein may serve as useful biomarkers to understand the mechanisms behind the development of fatigue. A longitudinal design exploring the association between changes in gene expression and fatigue symptoms of men with non-metastatic prostate cancer receiving external beam radiation therapy. Blood samples were collected from ten subjects at 7 timepoints for microarray analysis: baseline (before EBRT); days 1, 7, 14, 21, 42 of EBRT; and 30 days post-EBRT. Baseline data obtained from subjects were compared to data obtained from age-, race-, and gender-matched healthy controls.
Project description:Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). While monocytes/macrophages play major roles in both HIV- and TB-infection individually, a putative contribution of monocytes to the development of TB-IRIS remains unexamined. We performed a genome-wide array analysis on MOs purified from peripheral blood mononuclear cells (PBMCs) obtained before initiation of combined antiretroviral therapy (cART) to verify whether the transcriptome of MOs was already significantly modulated (even before receiving cART) in HIV+/TB+ patients who later developed TB-IRIS compared to control HIV+/TB+ patients who did not develop the complication . The subjects under study included a subset of 18 TB-IRIS patients and controls matched for age, gender and CD4 count.
Project description:immunotherapy offers a better prognosis for pancreatic cancer patients. As a direct extension of this work, various new therapy methods that are under exploration and clinical trials could be assessed or evaluated using the newly developed mathematical prognosis model.
Project description:Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor-κB ligand (RANKL) and is routinely administered to cancer patients to reduce the incidence of new bone metastasis. RANK-RANKL regulates bone turnover by controlling osteoclast recruitment, development, and activity. However, this interaction also can regulate a broad range of immune cells including dendritic cells and medullary thymic epithelial cells (mTECs). Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in cancer patients. Blood was collected from 23 prostate cancer patients and 3 renal cell carcinoma patients, who provided written informed consent, with advanced disease who were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of NK cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatment, can lead to the induction of immunologic checkpoints.
Project description:The clinical success of immune-checkpoint inhibitors (ICI) in both resected and metastatic melanoma has confirmed the validity of therapeutic strategies that boost the immune system to counteract cancer. However, half of patients with metastatic disease treated with even the most aggressive regimen do not derive durable clinical benefit. Thus, there is a critical need for predictive biomarkers that can identify individuals who are unlikely to benefit with high accuracy, so that these patients may be spared the toxicity of treatment without the likely benefit of response. Ideally, such an assay would have a fast turnaround time and minimal invasiveness. Here, we utilize a novel platform that combines mass spectrometry with an artificial intelligence-based data processing engine to interrogate the blood glycoproteome in melanoma patients before receiving ICI therapy. We identify 143 biomarkers that demonstrate a difference in expression between the patients who died within six months of starting ICI treatment and those who remained progression-free for three years. We then develop a glycoproteomic classifier that predicts benefit of immunotherapy (HR=2.7; p=0.026) and achieves a significant separation of patients in an independent cohort (HR=5.6; p=0.027). To understand how circulating glycoproteins may affect efficacy of treatment, we analyze the differences in glycosylation structure and discover a fucosylation signature in patients with shorter overall survival (OS). We then develop a fucosylation-based model that effectively stratifies patients (HR=3.5; p=0.0066). Together, our data demonstrate the utility of plasma glycoproteomics for biomarker discovery and prediction of ICI benefit in patients with metastatic melanoma and suggest that protein fucosylation may be a determinant of anti-tumor immunity.
Project description:Checkpoint blockade immunotherapy is a promising strategy in cancer treatment, depending on a favorable preexisting tumor immune microenvironment. However, prostate cancer is usually considered as an immune “cold” tumor with the poor immunogenic response and low density of tumor-infiltrating immune cells. This research uses samples from prostate cancer patients showing that docetaxel-based chemohormonal therapy reprograms the immune microenvironment and increases tumor-infiltrating T cells. Mechanistically, docetaxel treatment activates the cGAS/STING pathway and induces the type I interferon signaling, which may boost T cell-mediated immune response. In a murine prostate cancer model, chemohormonal therapy sensitizes tumor-bearing mice to PD1-blockade therapy. These findings demonstrate that docetaxel-based chemohormonal therapy activates prostate cancer immunogenicity and acts cooperatively with anti-PD-1 checkpoint blockade, providing a combination immunotherapy strategy that would lead to better therapeutic benefit for prostate cancer.