Emmanuel Katsanis
Work Summary
Augmenting immune responses to cancer. Reducing relapse and graft versus host disease after hematopoietic cell transplantation.
Augmenting immune responses to cancer. Reducing relapse and graft versus host disease after hematopoietic cell transplantation.
Immune-mediated destruction of haematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anaemia (aAA). Dysregulated CD8(+) cytotoxic T cells, CD4(+) T cells including T helper type 1 (Th1), Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NK T cells, along with the abnormal production of cytokines including interferon (IFN)-γ, tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β, induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF-β, IFN-γ and TNF-α genes, as well as certain human leucocyte antigen (HLA) alleles, may account for the propensity to immune-mediated killing of HSPCs and/or ineffective haematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure.
Tumour-derived chaperone-rich cell lysate (CRCL) when isolated from tumour tissue or when embedded with peptide antigens is a potent anti-cancer vaccine consisting of numerous chaperone/heat shock proteins, including the highly immunogenic Hsp70, Hsp90, glucose regulated protein 94, and calreticulin. We have previously documented that CRCL provides both a source of tumour antigens and danger signals triggering antigen presenting cell activation. In this report we describe the 'peptidome' of potential antigens extracted from CRCL prepared from a murine tumour. Using mass spectrometry techniques we identify almost 60 different proteins of origin for the CRCL peptides; we determine that the parental proteins come from essentially all parts of the cell, and are involved in a broad range of functions. Further in silico analysis demonstrates that the parental proteins are components of major signalling networks of vital importance for cancer cell survival, proliferation, and migration. In many instances the peptides identified possess amino acid sequences that would allow their putative binding and display by murine major histocompatibility complex class I and II molecules, and there are also predicted binding motifs for Hsp70-type chaperones. By mixing fractionated pools of peptides with antigen-free (normal liver) CRCL, we were able to reconstitute effective anti-tumour activity of the vaccine, showing that the peptides are indeed the major purveyors of CRCL vaccines' efficacy.
Hyperammonemia following hematopoietic cell transplantation (HCT) has been characterized as idiopathic and is associated with a very high mortality. A causal relationship between Ureaplasma infection and hyperammonemia in immunocompromised lung transplant recipients has recently been described. We document the first case of hyperammonemia following HCT associated with Ureaplasma parvum. The initiation of appropriate antibiotics resulted in rapid resolution of hyperammonemic encephalopathy and eradication of the implicating organism. This article is protected by copyright. All rights reserved.
Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood, and tumor beds. Furthermore, residual MDSC from doxorubicin-treated mice exhibited impaired suppressive function. Importantly, the frequency of CD4(+) and CD8(+) T lymphocytes and consequently the effector lymphocytes or natural killer (NK) to suppressive MDSC ratios were significantly increased following doxorubicin treatment of tumor-bearing mice. In addition, the proportion of NK and cytotoxic T cell (CTL) expressing perforin and granzyme B and of CTL producing IFN-γ was augmented by doxorubicin administration. Of therapeutic relevance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. These results thus indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T-cell-based immunotherapy.
This paper presents the treatment of a 12-year-old female spayed Great Dane who presented with vestibular signs (ataxia, nystagmus, hind end collapse). Thoracic radiographs revealed a discrete pulmonary nodule in the right cranial lung lobe. Ultrasound-guided fine needle aspirate detected primary bronchoalveolar adenocarcinoma, verified via computed tomography, with a second smaller nodule discovered in the right cranial lung lobe.