Engineering CD4+ T Cells to Enhance Cancer Immunity

This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has been paid to the role of CD8+ cytotoxic T cells in tumour protection, we provide convincing evidence that CD4+ helper T cells play a critical role in cancer immune responses in animal models and also in patients. We demonstrate that genetic engineering technologies provide exciting opportunities to extend the specificity range of CD4+ T cells from MHC class-II-presented epitopes to include peptides presented by MHC class I molecules. Functional enhancement of tumour immunity can improve the sensitivity of T cells to cancer antigens, promote survival in a hostile tumour microenvironment, boost cancer-protective effector mechanisms and enable the formation of T-cell memory. Engineered cancer-specific CD4+ T cells may contribute to protective immunity by a direct pathway involving cancer cell killing, and by an indirect pathway that boosts the function, persistence and memory formation of CD8+ T cells

Ashing of photoresists using dielectric barrier discharge cryoplasmas

Plasma ashing of photoresists is a critical step in advanced microelectronics manufacturing as it often leads to extensive damage in porous organosilicate low - κ dielectrics and hinders the use of highly porous films in interconnects. To reduce plasma damage, the authors investigated the feasibility of ashing a 248-nm photoresist with cryoplasma. The authors ashed photoresist-coated silicon wafers with dielectric barrier discharge microplasma generated at temperatures of 170-291 K, a pressure of 100 Torr, applied voltages of V appl = 0.8 - 1.6 kV, and a frequency of f = 20 kHz in both Ar / O 2 and Ar / O2/ N 2 gas mixtures. While the ashing rates at 170 K in Ar / O2 decreased to about 20% of the ashing rates achieved at room temperature and 240 K, the addition of N 2 to the plasma gas enhanced the ashing rates by a factor of 1.5-2. Optical emission spectroscopy measurements of the plasmas showed that, in the Ar / O2 / N 2 mixture, the main reactive species are N 2 radicals; x-ray photoelectron spectra of the ashed photoresists indicated that ashing is initiated from oxygen-containing functional groups of the photoresist. This study showed that decreased ashing rates at low plasma gas temperatures can be significantly enhanced by adjusting the plasma chemistry and that cryoplasma offers a viable process to minimize the damage from ashing of low - κ dielectric materials in interconnects, which will allow nanoelectronic devices to fully benefit from the introduction of such porous materials. © 2013 American Vacuum Society

Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression

Maturation of high-affinity B lymphocytes is precisely controlled during the germinal center reaction. This is dependent on CD4(+)CXCR5(+) follicular helper T cells (TFH) and inhibited by CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (TFR). Because NFAT2 was found to be highly expressed and activated in follicular T cells, we addressed its function herein. Unexpectedly, ablation of NFAT2 in T cells caused an augmented GC reaction upon immunization. Consistently, however, TFR cells were clearly reduced in the follicular T cell population due to impaired homing to B cell follicles. This was TFR-intrinsic because only in these cells NFAT2 was essential to up-regulate CXCR5. The physiological relevance for humoral (auto-)immunity was corroborated by exacerbated lupuslike disease in the presence of NFAT2-deficient TFR cells

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4(+) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Metaverse-Retail Service Quality: A Future Framework for Retail Service Quality in the 3D Internet

This paper argues that service quality in retailing in 3D Collaborative Virtual Environments (aka Metaverses) is distinct from service quality in the more familiar 2D mainly menu-driven web internet store (e-SQ). The study identifies and conceptualises the determinants of Metaverse Retailing service quality (MR-SQ) through a combination of focus groups and Critical Incident Technique. A set of four overarching determining elements of MR-SQ was revealed including customer service, product dimension, store dimension and 3D platform dimension. These incorporate some of the features found in 2D e-SQ but importantly the study indicated new characteristics, unique to MR-SQ. The CVE context presents opportunities for retailers in enhancing social experience, responsive service and creative co-production opportunities. It is within these gaps that respondents identified in 2D retailing that current CVEs and the future Web 3.0 hold appealing prospects for enhancing and producing creative and co-operative online retailing service quality (MR-SQ). The study provides a framework for guidance for retailers as well as for future research. Summary Statement of Contribution: The paper establishes new understanding of the determinants of Metaverse Retailing-Service Quality (MR-SQ). For virtual worlds in general and for service quality in particular, this study shows new MR-SQ dimensions, overlapping dimensions with different meanings to MR-SQ compares to e-SQ, and similar dimensions in both MR-SQ and e-SQ

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Expression of tumour-specific antigens underlies cancer immunoediting

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack1, 2. Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced2, 3. However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours4. Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.National Institutes of Health (U.S.) (Grant 1 U54 CA126515-01)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship AwardJohnD. Proctor FoundationDaniel K. Ludwig Schola