Biomedical subjects

Gavin P Dunn

Publications and source records attributed to Gavin P Dunn.

10 recordsLinked to original sources

PubMed2006

Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity.

Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology "cancer immunoediting" has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever-increasing experimental and clinical data that support the validity of this concept.

Animals↗

PubMed2006

Interferons, immunity and cancer immunoediting.

A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) - that is, the type I IFNs (IFNalpha and IFNbeta) and type II IFN (IFNgamma) - have emerged as central coordinators of tumour-immune-system interactions. Indeed, the decade-old finding that IFNgamma has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer immunoediting.

Animals↗

PubMed2006

Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection.

Herein we report the generation of mouse monoclonal antibodies (mAbs) specific for the IFNAR-1 subunit of the mouse interferon-alpha/beta (IFN-alpha/beta) receptor (MAR1 mAbs) that block type I IFN receptor signaling and biologic response induction in vitro and in vivo. These mAbs were generated from Ifnar1 (/) mice immunized by in vivo hydrodynamic transfection with a plasmid encoding the extracellular domain (ECD) of murine IFNAR-1. All MAR1 mAbs bound native receptor expressed on cell surfaces and immunoprecipitated IFNAR-1 from solubilized cells, and two mAbs also detected IFNAR-1 by Western blot analysis. in vitro, the mAbs prevented ligand-induced intracellular signaling and induction of a variety of type I IFN-induced biologic responses but had no effect on IFN-gamma-induced responses. The most effective in vitro blocker, MAR1-5A3, also blocked type I IFN-induced antiviral, antimicrobial, and antitumor responses in vivo. We also explored whether murine IFNAR-1 surface expression required the presence of Tyk2. In contrast to Tyk2-deficient human cell lines, comparable IFNAR-1 expression was found on primary cells derived either from wild-type or Tyk2 (/) mice. These mAbs represent much needed tools to more clearly elucidate the biochemistry, cell biology, and physiologic function of the type I IFNs and their receptor in mediating host-protective immunity and immunopathology.

Animals↗

PubMed2005

A critical function for type I interferons in cancer immunoediting.

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.

Animals↗

PubMed2005

IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression.

We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-gamma. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN-gamma receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN-gamma or IFN-alpha because of an impairment in the proximal signaling events downstream of both IFN-gamma and IFN-alpha/beta receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN-gamma and IFN-alpha/beta receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and histone deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.

Adenocarcinoma↗

PubMed2005

Interferon-gamma and cancer immunoediting.

Over the last 12 yr, we have shown that interferon-gamma and lymphocytes collaborate to regulate tumor development in mice. Specifically, we found that the immune system not only prevents the growth of primary (carcinogen-induced and spontaneous) and transplanted tumors but also sculpts the immunogenicity of tumors that form. These observations led us to refine the old and controversial "cancer immunosurveillance" hypothesis of Burnet and Thomas into one that we termed cancer immunoediting that better emphasizes the paradoxical host-protective and tumor-sculpting roles of immunity on developing tumors. Our current work focuses on defining the molecular mechanisms that underlie cancer immunoediting and exploring the implications of this process for cancer immunotherapy.

Animals↗

PubMed2004

The immunobiology of cancer immunosurveillance and immunoediting.

The last fifteen years have seen a reemergence of interest in cancer immunosurveillance and a broadening of this concept into one termed cancer immunoediting. The latter, supported by strong experimental data derived from murine tumor models and provocative correlative data obtained by studying human cancer, holds that the immune system not only protects the host against development of primary nonviral cancers but also sculpts tumor immunogenicity. Cancer immunoediting is a process consisting of three phases: elimination (i.e., cancer immunosurveillance), equilibrium, and escape. Herein, we summarize the data supporting the existence of each of the three cancer immunoediting phases. The full understanding of the immunobiology of cancer immunosurveillance and immunoediting will hopefully stimulate development of more effective immunotherapeutic approaches to control and/or eliminate human cancers.

Animals↗

PubMed2004

The three Es of cancer immunoediting.

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

Animals↗

PubMed2003

Murine cytomegalovirus paralyzes macrophages by blocking IFN gamma-induced promoter assembly.

Macrophages (M phi) are activated by IFN gamma and are important cellular targets for infection by human and murine cytomegalovirus (MCMV), making it advantageous for CMVs to block IFN gamma-induced M phi differentiation. We found that MCMV infection inhibited IFN gamma regulation of many genes in M phi. MCMV infection blocked IFN gamma responses at the level of transcription without blocking Janus kinase/signal transducer and activator of transcription pathway activation and targeted IFN response factor 1- and class II transactivator-dependent and independent promoters. MCMV did not alter basal transcription from IFN gamma-responsive promoters and left the majority of cellular transcripts unchanged even after 48 h of infection. The effects of MCMV infection were specific to chromosomal rather than transiently transfected promoters. Characterization of the IFN gamma-responsive chromosomal class II transactivator promoter revealed that MCMV infection blocked IFN gamma-induced promoter assembly, allowing the virus to transcriptionally paralyze infected M phi responses while allowing basal transcription to proceed.

Animals↗

PubMed2002

Cancer immunoediting: from immunosurveillance to tumor escape.

The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting. This process is responsible for both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts. In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction.

Animals↗