Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Chang, Chih Long; Hsu, Yun Ting; Wu, Chao; Yang, Yuh Cheng; Wang, Connie; Wu, Tian-Qin; Hung, Chien Fu

doi:10.4049/jimmunol.1103826

Cited by 71 publications

(47 citation statements)

References 50 publications

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“…7,11,22 Recently, wogonininduced early apoptotic ecto-CRT (Table 1) was also found to be mediated by PERK and PI3K. 58 Hence, in spite of this plasticity, the reliance of several ICD inducers on the ER stress sensor PERK as central 'DAMP-trafficking master' is noteworthy. Whether this is related to the archetypical induction of a viral response in the target cell (as described above), requiring the interface between PKR-mediated IFN response and PERK as ER stress sensor, 59,60 needs to be further explored.…”

Section: The Plasticity and Regulation Of Danger Signalling And Sensingmentioning

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: The Plasticity and Regulation Of Danger Signalling And Sensingmentioning

confidence: 99%

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

et al. 2013

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“…Other mechanisms of action by which bortezomib may kill cancer cells are through ER-stress and activation of the unfolded protein response (UPR) (57) and triggering apoptosis by preventing the degradation of pro-apoptotic proteins (56, 58). Some studies have shown that treatment of cancer cells using bortezomib increases surface expression of Hsp90 and Hsp60 in cancer cells leading to their more effective phagocytosis by dendritic cells (DCs), improving tumor vaccine effects (59). Bortezomib-treated mice also exhibit increased DC maturation and phagocytic potential (59).…”

Section: Standard Chemotherapeutic Drugs That Boost Ov Activity Throumentioning

confidence: 99%

“…Some studies have shown that treatment of cancer cells using bortezomib increases surface expression of Hsp90 and Hsp60 in cancer cells leading to their more effective phagocytosis by dendritic cells (DCs), improving tumor vaccine effects (59). Bortezomib-treated mice also exhibit increased DC maturation and phagocytic potential (59). On the other hand, one study found that bortezomib treatment leads to apoptosis of allo-reactive CD4+ T-cells.…”

Section: Standard Chemotherapeutic Drugs That Boost Ov Activity Throumentioning

confidence: 99%

Pharmacological Modulation of Anti-Tumor Immunity Induced by Oncolytic Viruses

2014

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Oncolytic viruses (OVs) not only kill cancer cells by direct lysis but also generate a significant anti-tumor immune response that allows for prolonged cancer control and in some cases cures. How to best stimulate this effect is a subject of intense investigation in the OV field. While pharmacological manipulation of the cellular innate anti-viral immune response has been shown by several groups to improve viral oncolysis and spread, it is increasingly clear that pharmacological agents can also impact the anti-tumor immune response generated by OVs and related tumor vaccination strategies. This review covers recent progress in using pharmacological agents to improve the activity of OVs and their ability to generate robust anti-tumor immune responses.

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“…The combination of arsenic and all-trans-retinoic acid is used against PML-RARα, and can modulate antigen presentation [129]. Bortezomib, an agent used for multiple myeloma that targets the proteasome and NF-κB, can affect numbers of CD8 + T cells and dendritic cells [130]. Erlotinib, a successful non-small cell lung cancer therapeutic that targets EGFR, can also induce an influx of dendritic cells [131].…”

Section: Targeted Oncogene Inactivation and Immune Response In Human mentioning

confidence: 99%

An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

Casey

Felsher

2014

Immunol Res

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Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often “oncogene addicted.” The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4+ T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shut down of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are not only involved in tumor initiation, tumor progression, and immunosurveillance, but are also involved in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

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Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Cited by 71 publications

References 50 publications

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

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

Pharmacological Modulation of Anti-Tumor Immunity Induced by Oncolytic Viruses

An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

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