Doctor of Philosophy, University Of The Negev (2012)
Edgar Engleman, Postdoctoral Faculty Sponsor
Immune cells function in an interacting hierarchy that coordinates the activities of various cell types according to genetic and environmental contexts. We developed graphical approaches to construct an extensible immune reference map from mass cytometry data of cells from different organs, incorporating landmark cell populations as flags on the map to compare cells from distinct samples. The maps recapitulated canonical cellular phenotypes and revealed reproducible, tissue-specific deviations. The approach revealed influences of genetic variation and circadian rhythms on immune system structure, enabled direct comparisons of murine and human blood cell phenotypes, and even enabled archival fluorescence-based flow cytometry data to be mapped onto the reference framework. This foundational reference map provides a working definition of systemic immune organization to which new data can be integrated to reveal deviations driven by genetics, environment, or pathology.
View details for DOI 10.1126/science.1259425
View details for PubMedID 26160952
Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.
View details for DOI 10.1038/nature14424
View details for Web of Science ID 000354040900041
View details for PubMedID 25924063
Early detection of colonic polyps can prevent up to 90% of colorectal cancer deaths. Conventional colonoscopy readily detects the majority of premalignant lesions, which exhibit raised morphology. However, lesions that are flat and depressed are often undetected using this method. Therefore, there is a need for molecular-based contrast agents to improve detection rates over conventional colonoscopy. We evaluated a quenched fluorescent activity-based probe (qABP; BMV109) that targets multiple cysteine cathepsins that are overexpressed in intestinal dysplasia in a genetic model of spontaneous intestinal polyp formation and in a chemically induced model of colorectal carcinoma. We found that the qABP selectively targets cysteine cathepsins, resulting in high sensitivity and specificity for intestinal tumors in mice and humans. Additionally, the qABP can be administered by either intravenous injection or by local delivery to the colon, making it a highly valuable tool for improved detection of colorectal lesions using fluorescence-guided colonoscopy.
View details for DOI 10.1016/j.chembiol.2014.11.008
View details for PubMedID 25579207
Although the IL-1α molecule has long been recognized, information about its distinct role in various diseases is limited, since most clinical studies have focused on the role of IL-1β. Despite triggering the same IL-1 receptor as does IL-1β, there is, however, a distinct role for IL-1α in some inflammatory diseases. IL-1α is a unique cytokine since it is constitutively present intracellularly in nearly all resting non-hematopoietic cells in health as well as being up-regulated during hypoxia. During cell necrosis, IL-1α functions as an alarm molecule and thus plays a critical role early in inflammation. Following its release from damage tissue cells, IL-1α mediates neutrophil recruitment to the site of injury, inducing IL-1β, other cytokines and chemokines from surrounding resident cells. Another unique attribute of IL-1α is its nuclear localization sequence present in the N-terminal half of the precursor termed the propiece. The IL-1α propiece translocates into the nucleus and participates in the regulation of transcription. Therefore, IL-1α, like IL-1 family members IL-33 and IL-37, is a 'dual-function' cytokine binding to chromatin as well as to its cell surface receptor. Some cancer cells can express membrane IL-1α, which can increase immunogenicity of tumor cells and serve in anti-tumor immune surveillance and tumor regression. However, in the tumor microenvironment, precursor IL-1α released from dying tumor cells is inflammatory and, similar to IL-1β, increases tumor invasiveness and angiogenesis.
View details for DOI 10.1016/j.smim.2013.10.005
View details for Web of Science ID 000330752000006
View details for PubMedID 24183701