Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression.

Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1.

Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia.

Targeting oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) in acute myeloid leukemia (AML) can reduce blast survival and tumor immune evasion. Decoy oligodeoxynucleotides (dODNs), which comprise STAT3-specific DNA sequences are competitive inhibition of STAT3 transcriptional activity. To deliver STAT3dODN specifically to myeloid cells, we linked STAT3dODN to the Toll-like receptor 9 (TLR9) ligand, cytosine guanine dinucleotide (CpG).

TLR9-Targeted SiRNA Delivery In Vivo.

The SiRNA strategy is a potent and versatile method for modulating expression of any gene in various species for investigational or therapeutic purposes. Clinical translation of SiRNA-based approaches proved challenging, mainly due to the difficulty of targeted SiRNA delivery into cells of interest and the immunogenic side effects of oligonucleotide reagents. However, the intrinsic sensitivity of immune cells to nucleic acids can be utilized for the delivery of SiRNAs designed for the purpose of cancer immunotherapy.

TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells.

Prostate cancer progression was associated with tumorigenic signaling activated by proinflammatory mediators. However, the etiology of these events remains elusive. Here, we demonstrate that triggering of the innate immune receptor, Toll-like Receptor 9 (TLR9), in androgen-independent prostate cancer cells initiates signaling cascade leading to increased tumor growth and progression.

TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients.

Purpose: Recent advances in immunotherapy of advanced human cancers underscored the need to address and eliminate tumor immune evasion. The myeloid-derived suppressor cells (MDSC) are important inhibitors of T-cell responses in solid tumors, such as prostate cancers. However, targeting MDSCs proved challenging due to their phenotypic heterogeneity.

Pazopanib as third line therapy for metastatic renal cell carcinoma: clinical efficacy and temporal analysis of cytokine profile.

Purpose: Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood.

MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu.

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.

Retracted: FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).

Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity.

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. We previously developed an immunostimulatory strategy based on targeted Stat3 silencing in Toll-like receptor 9 (TLR9)-positive hematopoietic cells using CpG-small interfering RNA (siRNA) conjugates. Here, we assessed the therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML).

TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.

Cancer radiotherapy may be immunogenic, but it is unclear why its immunogenic effects are rarely sufficient to prevent tumor recurrence. Here, we report a novel Toll-like receptor 9 (TLR9)-dependent mechanism that initiates tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed tumor recurrence in mouse models of B16 melanoma, MB49 bladder cancer, and CT26 colon cancer after localized high-dose tumor irradiation.

Calcarea carbonica induces apoptosis in cancer cells in p53-dependent manner via an immuno-modulatory circuit.

Background: Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. However, the molecular mechanisms underneath the anti-cancer effect, if any, of these medicines have still remained unexplored. To this end we attempted to evaluate the efficacy of calcarea carbonica, a homeopathic medicine, as an anti-cancer agent and to delineate the detail molecular mechanism(s) underlying calcerea carbonica-induced tumor regression.

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo.

STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells.

Tumor gangliosides and T cells: a deadly encounter.

Despite major advances in understanding the mechanisms of tumor immunity, its successful translation into effective tumor immunotherapy is hindered by the ability of tumors to foster a tolerant microenvironment and to activate a plethora of immunosuppressive mechanisms. Among different strategies employed by tumors to thwart immune responses, shedding of immunosuppressive molecules, such as sialic acid-containing glycosphingolipids, gangliosides, by the tumor is one important strategy. Aberrant and elevated expression of gangliosides has been demonstrated on the surface of cancer cells.

Curcumin: the multi-targeted therapy for cancer regression.

Tumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes and characterized by the deregulation of cell signaling pathways at multiple steps leading to cancer phenotype. Thus a proper management of tumorigenesis requires the development of multi-targeted therapies.

Curcumin enhances the efficacy of chemotherapy by tailoring p65NFκB-p300 cross-talk in favor of p53-p300 in breast cancer.

Breast cancer cells often develop multiple mechanisms of drug resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. High constitutive activation of NFκB has been found in different cancers, creating an environment conducive for chemotherapeutic resistance. Here we report that doxorubicin-induced SMAR1-dependent transcriptional repression and SMAR1-independent degradation of IkBα resulted in nuclear translocation of p65NFκB and its association with p300 histone acetylase and subsequent transcription of Bcl-2 to impart protective response in drug-resistant cells.

Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells.

Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein(s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis.

Theaflavins target Fas/caspase-8 and Akt/pBad pathways to induce apoptosis in p53-mutated human breast cancer cells.

The most common alterations found in breast cancer are inactivation or mutation of tumor suppressor gene p53. The present study revealed that theaflavins induced p53-mutated human breast cancer cell apoptosis. Pharmacological inhibition of caspase-8 or expression of dominant-negative (Dn)-caspase-8/Fas-associated death domain (FADD) partially inhibited apoptosis, whereas caspase-9 inhibitor completely blocked the killing indicating involvement of parallel pathways that converged to mitochondria.

Theaflavins retard human breast cancer cell migration by inhibiting NF-kappaB via p53-ROS cross-talk.

The present study demonstrates that theaflavins exploit p53 to impede metastasis in human breast cancer cells. Our data suggest that p53-dependent reactive oxygen species (ROS) induce p53-phosphorylation via p38MAPK in a feedback loop to inhibit IkappaBalpha-phosphorylation and NF-kappaB/p65 nuclear translocation, thereby down-regulating the metastatic proteins metalloproteinase (MMP)-2 and MMP-9. When wild-type p53-expressing MCF-7 cells are transfected with p53 short-interfering RNA, or treated with a pharmacological inhibitor of ROS, theaflavins fail to inhibit NF-kappaB-mediated cell migration.