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Hypoxia/HIF-1[alpha]- and extracellular adenosine/A2 adenosine receptor-mediated immunosuppression protects tissues from collateral damage by antipathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting antitumor immune cells in hypoxic and extracellular adenosine-rich tumors that are the most resistant to current therapies. Here, we explain a potentially novel, antiimmunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of antihypoxic oxygenation described here was motivated by the need to prevent the hypoxia/ HIF-1[alpha]-driven accumulation of extracellular adenosine to (a) unleash antitumor immune cells from inhibition by intracellular cAMP and (b) prevent immunosuppressive transcription of cAMP response element- and hypoxia response elementcontaining immunosuppressive gene products (e.g., TGF-[beta]). Use of oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes of clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanismbased approach to cancer immunotherapy described here., Introduction It has long been recognized that tumors are immunosuppressive, which explains the peaceful coexistence of tumors and tumor-reactive immune cells in the same cancer patient (the Hellstrom paradox) and [...]

FOR THOSE UNFAMILIAR WITH THE TERM 'INTEGRATIVE cancer care,' simply substitute 'integrative oncology,' 'complementary cancer care,' 'integrative whole person cancer care,' or even, over the protests of practitioners of 'integrative [...]

Cancer immunotherapy restores or enhances the effector function of CD8.sup.+ T cells in the tumour microenvironment.sup.1,2. CD8.sup.+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways.sup.3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide.sup.5,6. Although it has been investigated in vitro.sup.7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios.sup.9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8.sup.+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFN[gamma]) released from CD8.sup.+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system x.sub.c.sup.-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system x.sub.c.sup.- was negatively associated, in cancer patients, with CD8.sup.+ T cell signature, IFN[gamma] expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFN[gamma] and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach. Interferon-[gamma] induces ferroptotic cell death in tumours by suppressing cystine uptake and promoting lipid peroxidation., Author(s): Weimin Wang [sup.1] [sup.2] , Michael Green [sup.2] [sup.3] , Jae Eun Choi [sup.2] [sup.4] [sup.5] , Miguel Gijón [sup.6] , Paul D. Kennedy [sup.6] , Jeffrey K. Johnson [...]

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology.sup.1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance.sup.3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis.sup.8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy. A systematic proteomic investigation of disease mediators secreted by pancreatic stellate cells identifies leukaemia inhibitory factor (LIF) as a key factor that acts on cancer cells, promoting tumour progression and chemoresistance., Author(s): Yu Shi [sup.1] , Weina Gao [sup.2] [sup.3] , Nikki K. Lytle [sup.4] [sup.5] , Peiwu Huang [sup.2] [sup.3] [sup.6] , Xiao Yuan [sup.2] [sup.3] , Amanda M. Dann [...]

Mitochondrial metabolism is an attractive target for cancer therapy.sup.1,2. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC).sup.1,3. Here we show that BTB and CNC homology1 (BACH1).sup.4, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin.sup.5,6, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours.sup.7. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors. The transcription factor BACH1, which targets mitochondrial metabolism, is expressed at high levels in several types of cancer; reducing its expression in tumours makes them more susceptible to treatment with mitochondrial inhibitors., Author(s): Jiyoung Lee [sup.1] , Ali E. Yesilkanal [sup.1] , Joseph P. Wynne [sup.1] , Casey Frankenberger [sup.1] , Juan Liu [sup.2] , Jielin Yan [sup.1] , Mohamad Elbaz [sup.1] [...]

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose--and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated [NK.sup.+] and [CD3.sup.+] cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant [Box.sup.-/-] tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated [GFP.sup.+] NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy., Introduction We previously identified ONC201/TIC10 as a small molecule that upregulates endogenous TNF-related apoptosis-inducing ligand (TRAIL) in tumor and normal cells, and restores autocrine and paracrine antitumor activity within tumor [...]

The proteasomal system is a promising target for cancer treatment. Quercetin (Que), a flavonoid compound with antitumor ability, displays the inhibitory effect on proteasome activity. However, the underlying molecular mechanisms are ill defined. The present study found that Que treatment significantly reduced the chymotrypsin-like protease activity of proteasome whereas the trypsin- and caspase-like protease activities remained unchanged in HepG2 cancer cells, along with activation of p38 MAPK and JNK and reduction of ERK1/2 phosphorylation. Que-reduced proteasome activity could not be reverted by inhibition of p38 MAPK and JNK signaling pathway. In addition, MEK1 overexpression or knockdown upregulated or downregulated the chymotrypsin-like protease activity of proteasome, respectively. Both Que and MEK1/ERK1/2 inhibitor attenuated the expression levels of proteasome p subunits. These results indicate that Que-induced suppression of MEK1/ERK1/2 signaling and subsequent reduction of proteasome p subunits is responsible for its inhibitory impacts on proteasome activity. Key words: quercetin, proteasome, MEK1/ERK1/2 signaling pathway, HepG2 cells. Le systeme proteasomal est une cible prometteuse pour le traitement du cancer. La quercetine (Que), un compose flavonoide avec des proprietes antitumorales, presente un effet inhibiteur sur l'activite du proteasome. Toutefois, les modes d'action moleculaires sous-jacents ne sont pas bien caracterises. La presente etude a montre que la Que entrainait une diminution marquee de l'activite proteasique s'apparentant a celle de la chymotrypsine, alors que l'activite proteasique s'apparentant a celles de la trypsine et de la caspase demeurait inchangee pour les cellules cancereuses HepG2, avec une activation des kinases p38 MAPK et JNK, ainsi qu'une diminution de la phosphorylation d'ERK1/2. La reduction de l'activite du proteasome par la Que ne pouvait pas s'inverser par l'inhibition des voies de signalisation de p38 MAPK et de JNK. De plus, la surexpression ou la repression (<< knock-down >>) du gene MEK1 entrainait une regulation respectivement a la hausse ou a la baisse de l'activite de protease s'apparentant a celle de la chymotrypsine du proteasome. Tant la Que que l'inhibiteur de la voie MEK1/ERK1/2 entrainaient une attenuation des taux d'expression de sous-unites p du proteasome. Ces resultats montrent que l'inhibition de la voie de signalisation MEK1/ERK1/2 par la Que, avec la reduction subsequente des taux de sous-unites p du proteasome, est responsable de son incidence inhibitrice sur l'activite du proteasome. [Traduit par la Redaction] Mots-cles : quercetine, proteasome, voie de signalisation MEK1/ERK1/2, cellules HepG2., Introduction The proteasomal system plays a critical role in regulating cellular function and maintaining intracellular protein homeostasis through modulating protein ubiquitination and degrading mis-folded or deleterious proteins by proteolysis, respectively. [...]

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV- PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, [CD8.sup.+] T cell depletion, IFN-[gamma] neutralization, or implantation of tumors in IFN-[gamma] receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting [CD8.sup.+] T cell accumulation and IFN-[gamma] production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness., Introduction Recent advances in cancer immunotherapy have revolutionized cancer treatment. Immune checkpoint blockade (ICB), designed to target immune suppressive signals such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed [...]

Author(s): Jinfang Zhang [1]; Xia Bu [2]; Haizhen Wang [3]; Yasheng Zhu [4]; Yan Geng [3]; Naoe Taira Nihira [1]; Yuyong Tan [1, 5]; Yanpeng Ci [1, 6]; Fei Wu [...]

The immune system has an essential underlying role in both physiological and pathological conditions. The immune response is the result of the complex interaction of inflammatory cells and circulating humoral [...]

Attempts to boost the body's antitumour immune responses can trigger a harmful inflammatory reaction called a cytokine storm. New insights into the mechanisms involved might help to prevent this problem.Catecholamine molecules have a role in a harmful inflammatory response., Author(s): Stanley R. RIddellAuthor Affiliations:Adrenaline fuels a cytokine storm during immunotherapy When immune cells recognize a molecule that indicates a possible threat, they release cytokines that promote inflammation and orchestrate [...]

'Plants have been used as medicines since the dawn of animal life. The initial use of plants as medicines by humans is thought to have been a result of 'instinctive' [...]

Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants., Introduction Frontline cancer treatments like radiation and chemotherapy systemically interrupt critical cell processes and thus produce serious side effects, so there is considerable interest in developing immune-based treatments that can [...]

Byline: Sushma. Bhatnagar India is the second-most populous country in the world and contributes to 17% of the global population. India is aging rapidly. The elderly will constitute 10% of [...]