11 research outputs found
Heat Shock Protein (HSP) peptide and HSP-based immunotherapies for the treatment of cancer
No full textIntracellular residing heat shock proteins (HSPs) with a molecular weight of approximately 70 and 90 kDa function as molecular chaperones that assist folding/unfolding and transport of proteins across membranes and prevent protein aggregation after environmental stress. In contrast to normal cells, tumor cells have higher cytosolic HSP70 and Hsp90 levels which contribute to tumor cell propagation, metastasis and protection against apoptosis. In addition to their intracellular chaperoning functions, extracellular localized and membrane-bound HSPs have been found to play key roles in eliciting anti-tumor immune responses either by acting as carriers for tumor-derived, immunogenic peptides, as adjuvants for antigen presentation or as targets for the innate immune system. The interaction of HSP-peptide complexes or peptide-free HSPs with receptors on antigen presenting cells (APCs) promotes the maturation of dendritic cells (DCs), results in an up-regulation of MHC class I and class II molecules, induces secretion of pro- and anti-inflammatory cytokines, chemokines, and immune modulatory nitric oxides and thus integrate adaptive and innate immune phenomena. Herein, we aim to recapitulate the history and current status of HSP-based immunotherapies and vaccination strategies in the treatment of cancer
Radiation-induced changes in microcirculation and interstitial fluid pressure affecting the delivery of macromolecules and nanotherapeutics to tumors
No full textThe immature, chaotic microvasculature of most solid tumors can present a significant impediment to blood-borne delivery, uneven distribution and compromised penetration of macromolecular anticancer drugs and diagnostic agents from tumor microvessels across the interstitial space to cancer cells. To reach viable tumor cells in relevant concentrations, macromolecular agents are confronted with several barriers to vascular, transvascular and interstitial transport. Amongst those (a) heterogeneous and poor blood supply, (b) distinctly reduced or even abolished hydrostatic and oncotic pressure gradients across the microvessel wall abrogating the convective transport from the vessel lumen into the interstitial space (impairment of transvascular transport), and (c) impediment of convective transport within the interstitial compartment due to elevated interstitial fluid pressure (resulting from hyperpermeable blood vessels coupled with non-functional lymphatics) and a dense structure of the interstitial matrix are the major mechanisms hindering drug delivery. Upon irradiation, changes in these barrier functions are inconclusive so far. Alterations in vascular transport properties following fractionated radiation up to 40 Gy are quite inconsistent in terms of direction, extent and time course. Total doses above 45 Gy can damage tumor microvessels, additionally impeding vascular delivery. Vascular permeability for macromolecules might be enhanced up to a total dose of 45 Gy. However, this effect is counteracted/abolished by the elevated interstitial fluid pressure (IFP) in solid tumors. When assessing IFP during fractionated radiotherapy in patient tumors, inconsistent alterations have been observed, both in direction and extent. From these data it is concluded that modulations in vascular, transvascular and interstitial transport by irradiation of solid tumors are rather unclear so far. Translation of experimental data into the clinical setting thus needs to be undertaken
Non-targeted effects of photon and particle irradiation and the interaction with the immune system
No full textIonizing irradiation is an important clinical approach to treat solid tumors. Modern radiation technologies aim to selectively kill tumor cells and protect the surrounding normal tissue. The standard paradigm for radiation effects in cellular systems involves damage of the DNA including DNA double strand breaks, which are considered as most effective in destroying tumor cells. Due to their enhanced physical and radiobiological properties, high linear energy transfer (LET) radiation qualities are of special interest in tumor therapy. Future radiation therapy strategies aim to utilize carbon ions to effectively treat highly aggressive tumors. More recently, evidence is emerging for non-DNA targeted effects of radiation, including mutations, chromosomal aberrations and changes in gene expression, which can occur in cells that were not directly exposed to radiation. Radiation oncologists are only gradually beginning to appreciate the clinical relevance of radiation-induced bystander effects, genomic instability and abscopal effects. Since these effects are sensed by the immune system, a combination of immunotherapy and irradiation presents a new therapeutic opportunity in the future
Radiation, inflammation and immune responses in cancer
No full textChronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As disussed in this review, ionizing radiation leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-kB, STAT-3 and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signalling pathways induced by ionizing radiation offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to ionizing radiation
Chronic Inflammation in cancer development
No full textChronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-B, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-B interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression and metastatic spread. IL-1, IL-6, TNF and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions
Frontiers Research Topics OncologyFrontiers Research Topic: Radiation-induced effects and the immune system
No full textInfluence of tumours on protective anti-tumour immunity and the effects of irradiation
No full textInnate and adaptive immunity play important roles in the development and progression of cancer and it is becoming apparent that tumours can influence the induction of potentially protective responses in a number of ways. The prevalence of immunoregulatory T cell populations in the circulation and tumours of patients with cancer is increased, and the presence of these cells appears to present a major barrier to the induction of tumour immunity. One aspect of tumour-mediated immunoregulation which has received comparatively little attention is that which is directed towards natural killer (NK) cells, although evidence that the phenotype and function of NK cell populations are modified in patients with cancer is accumulating.Although the precise mechanisms underlying these localised and systemic immunoregulatory effects remain unclear, tumour-derived factors appear, in part at least, to be involved. The effects could be manifested by an altered function and/or via an influence on the migratory properties of individual cell subsets. A better insight into endogenous immunoregulatory mechanisms and the capacity of tumours to modify the phenotype and function of innate and adaptive immune cells might assist the development of new immunotherapeutic approaches and improve the management of patients with cancer.This article reviews current knowledge relating to the influence of tumours on protective anti-tumour immunity and considers the potential influence that radiation-induced effects might have on the prevalence, phenotype and function of innate and adaptive immune cells in patients with cancer
Heat shock protein 70 (Hsp70) serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma
No full textMembers of the heat shock protein 70 (HSP70) family play an important role in assisting protein folding, preventing protein aggregation and transport of proteins across membranes under physiological conditions. Following environmental (i.e. irradiation, chemotherapy), physiological (i.e. cell growth, differentiation) and pathophysiological (i.e. inflammation, tumorigenesis) stress, the synthesis of HSPs is highly up-regulated, whereas protein synthesis in general is reduced. In contrast to normal cells, many tumor entities including hepatocellular carcinomas (HCC) overexpress Hsp70, the major-stress-inducible member of the HSP70 family, present it on their cell surface and secrete it into the extracellular milieu. Herein, the prognostic relevance of serum Hsp70 levels in patients with chronic hepatitis (CH; n=50), liver cirrhosis (LC; n=46), and hepatocellular carcinoma (HCC; n=47) was analyzed. Similar to other tumor entities, Hsp70 is also present on the surface of primary HCC cells. The staining intensity of intracellular Hsp70 in HCC tissue is stronger compared to control and cirrhotic liver sections. Hsp70 serum levels in all HCC patients were significantly higher compared to a control group without liver disease (n=40). No significant age- and gender-related differences in Hsp70 serum levels were observed in male and female healthy human volunteers (n=86). Patients with chronic hepatitis (CH, n=50) revealed significantly higher Hsp70 serum levels compared to the control group, however, these values were significantly lower than those of HCC patients (n=47). Furthermore, a subgroup of patients with LC who subsequently developed HCC (LC-HCC, n=13) revealed higher Hsp70 serum levels than patients with LC (n=46, p=0.05). These data indicate that serum Hsp70 levels are consecutively increased in patients with chronic hepatitis, liver cirrhosis and liver carcinomas and thus might have a prognostic value
Correlation of Hsp70 serum levels with gross tumor volume and composition of lymphocyte subpopulations in patients with squamous cell and adeno non-small cell lung cancer
No full textHeat shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor, on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D and natural cytotoxicity receptors (NCRs; NKp44, NKp46, NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after RCT at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume (GTV) was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that the innate immune system might get activated by soluble Hsp70 in squamous cell but not adeno NSCLC
Review article: Heat shock protein 70 (Hsp70) peptide activated Natural Killer (NK) cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCTx) – from preclinical studies to a clinical phase II trial
No full textHeat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and NSCLC in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2015. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum based radiochemotherapy with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with radiochemotherapy alone. As secondary endpoints overall survival, toxicity, quality-of-life and biological responses will be determined in both study groups
