CD91-dependent programming of T-helper cell responses following heat shock protein immunization

Pawaria, Sudesh; Binder, Robert J.

doi:10.1038/ncomms1524

Cited by 179 publications

(167 citation statements)

References 52 publications

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“…6,7,37 Moreover, ecto-CRT can incite the production of both IL-6 and tumour necrosis factor (TNF) from DCs and facilitate T helper type 17 (Th17) polarization. 38 Similarly, ecto-HSP90 has been demonstrated to be a crucial mediator of immunogenicity, especially in the case of bortezomib-induced ICD. 35 During anti-cancer DC vaccination based on ICD, ecto-HSP90 correlates better (or at least as strongly as ecto-CRT) with the ability of patients to respond to vaccination.…”

Section: Viral Response and Icd: A New Connection?mentioning

confidence: 99%

Danger signalling during cancer cell death: origins, plasticity and regulation

et al. 2013

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Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these. The ultimate outcome of an immune response to cancer cell death (i.e., anti-tumourigenic, pro-tumourigenic or autoimmunity or different combinations of these) tends to be complex and may depend on a number of factors like the type of the cancer cells that die and their in vivo location, the type of cell death pathway they follow to die, the types of immune cells that phagocytose them or interact with them and, last but not the least, whether a cancer antigen is recognized or not. Tolerogenicity towards cell death, as happens predominantly when cancer cells undergo physiological apoptosis (after treatment with most anti-cancer therapies), depends on a number of factors including the presence of immunosuppressive factors, absence or inactivation of DAMPs, induction of tolerogenic dendritic cells (DCs), 'suboptimal' activation of CD8 þ T cells only and apoptotic 'mimicry'.Accentuated immunogenicity exhibited by cancer cells undergoing immunogenic cell death (ICD; after treatment with selected anti-cancer therapies), depends on a number of factors like emission of DAMPs (i.e., surface exposure of certain chaperones, secretion or release of certain nucleotides and endokines), presence of immunostimulatory factors, induction of DC maturation (both phenotypic and functional) and optimal activation of CD4 þ ab, CD8 þ ab and gd T-cell responses. Certain DAMPs are actively trafficked during ICD by danger signalling pathways, which are instigated and regulated by a complex interplay between endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production and cert...

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Section: Viral Response and Icd: A New Connection?mentioning

confidence: 99%

Danger signalling during cancer cell death: origins, plasticity and regulation

et al. 2013

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“…38,52,64 Ecto-CRT elicits the production of pro-inflammatory cytokines, such as interleukin (IL)-6 and tumour necrosis factor-α (TNF-α) from DCs, thereby facilitating Th1 and/or Th17 polarization. 65,36 Moreover, overall expression of CRT mRNA (CALR) in tumour tissue samples (derived from ovarian or lung cancer patients treated with paclitaxel or radiotherapy, respectively) linearly correlates with the levels of genes coding for phagocytosis-related proteins (involved in phagosome maturation or degradation). 52 In fact, dying cancer cells naturally incapable of presenting ecto-CRT (owing to an intrinsic resistance mechanism) fail to mediate an anticancer vaccination effect.…”

Section: Regulated Necrosismentioning

confidence: 99%

“…52 Similarly, HSP90-CD91 binding on immune cells facilitates DC maturation and Th1/17 priming. 65 In some contexts, ecto-HSP90 and ecto-CRT are interchangeable in mediating immunogenicity; 66 while in other cases, ecto-CRT is the superior immunogenic signal. 56 In fact, an in silico analysis suggests that CRT (but not HSP90) possesses close homologues of crucial phagocytosis-assisting motifs.…”

Section: Regulated Necrosismentioning

confidence: 99%

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

et al. 2016

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Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of 'eat me' signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.

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“…Thus, the increased expression of CD86 without change in CD80 status may rather represent a different basal functional characteristics of cDCs than a sign of undergoing proinflammatory stimulation. Also, the increased expression of CD91, molecule known to act as heat shock protein receptor involved in cross presentation and T cell priming [22], may influence the basic ability and readiness of peripheral blood cDCs to react upon danger signal encounter. Taking together, these observations may suggest that thyrometabolic parameters affect in an unspecific manner immune parameters in the periphery, including modulation of various DC populations.…”

Section: Discussionmentioning

confidence: 99%

Effect of L-thyroxine treatment on peripheral blood dendritic cell subpopulations in patients with Hashimoto’s thyroiditis

Stasiołek

Dedecjus

Adamczewski

et al. 2014

Folia Histochem Cytobiol.

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Recent reports suggested dendritic cells (DCs) to be important players in the pathogenesis of autoimmune thyroid processes in humans. However, there are virtually no data addressing the influence of thyroid autoaggression-associated disturbances of thyrometabolic conditions on DCs biology. The aim of the study was to evaluate the influence of L-thyroxine supplementation on conventional and plasmacytoid peripheral blood DCs subtypes in patients with hypothyroidism due to Hashimoto's thyroiditis (HT). Eighteen patients with newly diagnosed hypothyroidism due to HT were included into the study. All patients received L-thyroxine treatment with doses adjusted to reach euthyroidism. Peripheral blood DC subtypes structure and immunoregulatory phenotype were analyzed by flow cytometry in the same patient prospectively at two time points: (i) before and (ii) 3 months after beginning of L-thyroxine treatment (hypothyroidism vs. euthyroidism, respectively). Percentage of plasmacytoid DCs in peripheral blood mononuclear cells fraction was significantly decreased in the course of L-thyroxine treatment (0.27 ± 0.19 vs. 0.11 ± 0.08; p < 0.05), whereas we did not observe any changes in the number of conventional DCs. However, the phenotypic analysis showed a significant increase of conventional DCs expressing CD86 and CD91 (64.25 ± 21.6% vs. 86.3 ± 11%; p < 0.05 and 30.75 ± ± 11.66% vs. 44.5 ± 13.3%; p < 0.05; respectively) in euthyroid patients. Standard L-thyroxine supplementation in HT patients exerted significant immunoregulatory effects, associated with quantitative and phenotypic changes of peripheral blood DC subpopulations.

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CD91-dependent programming of T-helper cell responses following heat shock protein immunization

Cited by 179 publications

References 52 publications

Danger signalling during cancer cell death: origins, plasticity and regulation

Danger signalling during cancer cell death: origins, plasticity and regulation

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

Effect of L-thyroxine treatment on peripheral blood dendritic cell subpopulations in patients with Hashimoto’s thyroiditis

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