19 research outputs found
Chemoattractant receptors BLT1 and CXCR3 regulate anti-tumor immunity by facilitating CD8+ T cell migration to tumors.
No full textPresence of increased numbers of CD8+ T cells in the tumors correspond to better overall survival in the patients. Variety of immuno-therapies have shown considerable efficacy in the clinic, however, a multitude of patients remain unresponsive. Most of these immunotherapies rely on effector T cell responses in the tumor. A major obstacle in the success of these immunotherapies is poor recruitment of CD8+ T cells into tumors despite intact effector responses in the periphery. Therefore understanding the mechanisms that regulate CTL infiltration into tumors becomes essential. Previous studies in our laboratory suggested an important role for BLT1 in immune surveillance against tumors by regulating CTL migration in a syngeneic cervical cancer tumor model. In this thesis, we investigated the roles of leukotriene B4 (LTB4) receptor - BLT1; and CXCR3, the receptor for CXCL9, CXCL10 and CXCL11 in anti-tumor immunity using a syngeneic B16 melanoma tumor model. BLT1-/- mice and CXCR3-/- mice on a C57BL/6 background were used to examine the function of these receptors in tumor progression. Significant acceleration in tumor growth and reduced survival was observed in both BLT1-/- and CXCR3-/- mice as compared to the WT mice. Analysis of tumor infiltrating leukocytes revealed significant reduction of CD8+ T cells in the tumors of BLT1-/- and CXCR3-/- mice as compared to WT tumors; their frequencies being similar in the periphery (spleen and TdLN). Significant reduction of Granzyme-B and IFNγ transcripts were observed in tumors of knockout mice compared to WT mice. Adoptive transfer of tumor experienced WT but not BLT1-/- or CXCR3-/- CD8+ T cells reduced tumor growth significantly in Rag2-/- mice, which correlated with reduced infiltration of knockout CD8+ T cells into tumors. Co-transfer of WT CD8+ T cells with either of the knockout CD8+ T cells in tumor bearing Rag2-/- mice showed that WT CD8+ T cells did not facilitate additional knockout CD8+ T cell infiltration to tumors. BLT1/CXCR3 double deficient mice displayed similar tumor kinetics as single knockout mice and showed lack of synergism. The requirement for BLT1 and CXCR3 in inducing checkpoint blockade mediated anti-tumor response was tested. While anti-PD-1 based vaccine significantly attenuated tumor growth in WT mice, the vaccine completely lost its efficacy in BLT1-/-, CXCR3-/- or BLT1-/-CXCR3-/- mice that correlated with failure of knockout CD8+ T cell infiltration into tumors. These results demonstrate a critical role for BLT1 and CXCR3 in CTL migration to tumors and thus can be targeted to enhance effective anti-tumor responses
Immunotherapy of Primary Brain Tumors: Facts and Hopes
No full textAbstract
The field of cancer immunotherapy has made exciting progress for some cancer types in recent years. However, recent failures of late-phase clinical trials evaluating checkpoint blockade in patients with glioblastoma (GBM) represent continued challenges for brain cancer immunotherapy. This is likely due to multiple factors including but not limited to marked genetic and antigenic heterogeneity, relatively low mutational loads, and paucity of GBM-infiltrating T cells. We review recent and ongoing studies targeting the checkpoint molecules as monotherapy or in combination with other modalities, and discuss the mechanisms underlying the unresponsiveness of GBM to single-modality immunotherapy approaches. We also discuss other novel immunotherapy approaches that may promote T-cell responses and overcome the “cold tumor” status of GBM, including oncolytic viruses and adoptive T-cell therapy. Clin Cancer Res; 24(21); 5198–205. ©2018 AACR.</jats:p
Circular Communities For Housing: Transforming waste plastic and glass into building blocks making housing construction simpler, cheaper, faster and more sustainable
No full textIndonesia is one of the 5 countries in the world that contribute to around 60% of all the ocean plastics in the world. This thesis project is based in the kampungs of Cigondewah, in Bandung, Indonesia. This project tries to deal with the local economies of waste recycling and the informal housing industry. The kampungs are situated next to a major textile factory PT Kahatex that provide jobs to most of the people in the Kampungs. The informal recycling industry also heavily depends on the waste produced from these factories. The idea is to create a decentral circular economy with a collaboration of the building and recycling industry, to develop building materials out of waste plastic. Wastes that are sourced locally can be upcycled into simple and long lasting elements that can provide for affordable and sustainable housing for the low-income population of the kampungs.Architecture, Urbanism and Building Science
Abstract 3767: Identification of a novel and a shared H3.3K27M mutation derived neoantigen epitope and H3.3K27M specific TCR engineered T cell therapy for glioma
No full textAbstract
Brain cancers are the leading cause of cancer related mortality in children and young adults with median overall survival of 9-10 months and hence represents a significant unmet medical need. Genome-wide sequencing efforts of pediatric gliomas have identified a recurrent and shared missense mutation in the gene encoding the replication-independent variant of histone 3, H3.3. Approximately 70% of diffuse intrinsic pontine gliomas (DIPG) and 50% of thalamic and other midline gliomas harbor the amino acid substitution from lysine (K) to methionine (M) at the position 27 of H3.3 gene. Tumor specific missense mutations are not subjected to self-tolerance and can be suitable targets (neoantigens) for cancer immunotherapy. Herein, we evaluated whether the H3.3K27M mutation can induce specific cytotoxic T lymphocyte (CTL) response in HLA-A2+ T cells. In vitro stimulation of HLA-A2+ donor derived CD8+ T cells with a synthetic peptide encompassing the H3.3K27M mutation (H3.3K27M epitope) induced CTL lines which recognized not only T2 cells loaded with the synthetic H3.3K27M epitope peptide but also lysed the HLA-A2+ DIPG cells which endogenously harbor the H3.3K27M mutation. On the other hand, the CTL lines did not react to either HLA-A2+ but H3.3K27M- negative DIPG cell lines or H3.3K27M positive but HLA-A2 negative DIPG cells. The H3.3K27M epitope peptide but not the non-mutant counterpart indicated an excellent binding affinity (Kd 151nM) to HLA-A2 based on competitive binding inhibition assay. From CTL clones with high and specific affinities to HLA-A2-H3.3K27M-tetramer, cDNAs for T cell receptor (TCR) alpha and beta chains were cloned into a retroviral vector. Human HLA-A2+ T cells transduced with the TCR demonstrated antigen specific reactivity as well as anti-glioma responses in vitro. Peptide titration assays suggested that the H3.3K27M specific TCR had the half-maximal reactivity for peptide recognition of around 100nM. Furthermore, critically important for safety of clinical application, alanine scanning demonstrated that the key amino acid sequence motif in the epitope of the TCR reactivity is not shared by any known human protein. Finally, intravenous administration of T cells transduced with H3.3K27M specific TCR significantly inhibited the growth of intracranial HLA-A2+ H3.3K27M positive glioma xenografts in immune deficient NSG mice. These data provide us with a strong basis for developing peptide based vaccines as well as adoptive transfer therapy using autologous T cells transduced with the H3.3K27M specific TCR.
Acknowledgements: This study is supported by the NIH/NINDS (1RO1NS096954), V Foundation and Parker Institution for Cancer Immunotherapy.
Citation Format: Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Naznin Jahan, Diego Carrera, Payal Watchmaker, Kira Downey, Shuming Liu, Shruti Shrivastav, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada. Identification of a novel and a shared H3.3K27M mutation derived neoantigen epitope and H3.3K27M specific TCR engineered T cell therapy for glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3767. doi:10.1158/1538-7445.AM2017-3767</jats:p
Correspondence on 'H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma' by Immisch et al
No full text
A spontaneous metastasis model reveals the significance of claudin-9 overexpression in lung cancer metastasis
No full textFabrication of homogeneous and heterogeneous surface enhanced Raman spectroscopy substrates for the detection of genetic biomarkers of diseases
No full textThe demand for cost-effective, rapid, and precise diagnostic tools for genetic diseases, such as cancer, remains unmet. Detecting mutations in disease-specific micro-RNA biomarkers presents a promising avenue for early disease screening. Liquid biopsy-based noninvasive diagnostic methods are gaining traction. Surface-enhanced Raman spectroscopy (SERS), renowned for its sensitivity, specificity, and multiplexed analysis capabilities, stands out for identifying single-base variations in nucleic acid sequences. Our hypothesis centers on leveraging SERS to detect nucleotide changes, like substitution or transposition, within these sequences. To this end, a homogeneous SERS substrate comprising colloidal silver nanospheres was meticulously developed and optimized via wet chemical synthesis. This substrate showcases homogeneity in particle size, optimal nanoparticle-analyte interaction, and substantial SERS signal enhancement. Our analysis of short single-stranded DNA and RNA sequences using this platform revealed its sensitivity in detecting single-base changes, reflecting as shifts in spectral peak intensity or position. To enhance the platform's efficiency in discerning oligonucleotide changes, we employed a Gaussian process-based hypothesis testing algorithm. This approach achieved a remarkable 95% accuracy in distinguishing between two nucleic acid analytes. Integrating SERS with machine learning proved highly sensitive in detecting sequential changes in the well-established prostate cancer biomarker, micro-RNA miR-21, thus validating the SERS platform's diagnostic potential. Moreover, beyond colloidal silver nanoparticles, we engineered a heterogeneous SERS substrate comprising a uniformly arranged array of gold nanostars. The three step-based bottom-up fabrication method used to develop the heterogenous substrate was highly cost-effective and resulted in nanoparticle arrangement precision similar to top-down lithographic techniques, which enables exceptional SERS enhancement for the analysis of oligonucleotides, offering reusability and maintaining stability over extended periods. Our work meticulously details the successful fabrication of SERS substrates and their application in detecting alterations in nucleic acid sequences. This research underscores the promising prospects of SERS-based platforms for diagnostic applications.Ph.D.Includes bibliographical reference
Energy-Efficient Hardware Data Prefetching
No full textExtensive research has been done in prefetching techniques that hide memory latency in microprocessors leading to performance improvements. However, the energy aspect of prefetching is relatively unknown. While aggressive prefetching techniques often help to improve performance, they increase energy consumption by as much as 30% in the memory system. This paper provides a detailed evaluation on the energy impact of hardware data prefetching and then presents a set of new energy-aware techniques to overcome prefetching energy overhead of such schemes. These include compiler-assisted and hardware-based energy-aware techniques and a new power-aware prefetch engine that can reduce hardware prefetching related energy consumption by 7-11x. Combined with the effect of leakage energy reduction due to performance improvement, the total energy consumption for the memory system after the application of these techniques can be up to 12% less than the baseline with no prefetching
