Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells ...and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.
We study chiral partner structure of four light nucleons, N(939), N(1440), N(1535) and N(1650), using an effective chiral model based on the parity doublet structure. In our model we introduce four ...chiral representations, (1,2), (2,1), (2,3) and (3,2), under SU(2)L⊗SU(2)R symmetry. We determine the model parameters by fitting them to available experimental values of masses, widths and the axial charge of N(939) together with the axial charges of N(1535) and N(1650) by lattice analyses. We find five groups of solutions: In a group the chiral partner to N(939) is N(1440) having small chiral invariant mass. In another group, the chiral partner is a mixture of N(1535) and N(1650) having a large chiral invariant mass. Using the solutions, we give phenomenological predictions on the axial charges and changes of masses associated with chiral symmetry restoration.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes ...increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail ...to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.
Immune-checkpoint blockers are at the forefront of cancer immunotherapy, yet they fail to control neoplasia in most patients. Pitt et al. discuss the diverse influences responsible for the heterogeneity in treatment responses by focusing on the newfound impact of host microbiota.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Type I interferon (IFN) release by irradiated cancer cells is paramount for radiation therapy to elicit anticancer immunity. Our findings demonstrate that mitochondrial outer membrane ...permeabilization (MOMP) triggered by RT enables exposure of mitochondrial DNA to the cytosol, hence setting off CGAS-driven type I IFN synthesis. These data point to the existence of a therapeutically actionable mitochondrial checkpoint that restricts innate immune signaling in irradiated cancer cells.
DNA origami involves the folding of long single-stranded DNA into designed structures with the aid of short staple strands; such structures may enable the development of useful nanomechanical DNA ...devices. Here we develop versatile sensing systems for a variety of chemical and biological targets at molecular resolution. We have designed functional nanomechanical DNA origami devices that can be used as 'single-molecule beacons', and function as pinching devices. Using 'DNA origami pliers' and 'DNA origami forceps', which consist of two levers ~170 nm long connected at a fulcrum, various single-molecule inorganic and organic targets ranging from metal ions to proteins can be visually detected using atomic force microscopy by a shape transition of the origami devices. Any detection mechanism suitable for the target of interest, pinching, zipping or unzipping, can be chosen and used orthogonally with differently shaped origami devices in the same mixture using a single platform.
Neoantigens generated by somatic nonsynonymous mutations are key targets of tumor-specific T cells, but only a small number of mutations predicted to be immunogenic are presented by MHC molecules on ...cancer cells. Vaccination studies in mice and patients have shown that the majority of neoepitopes that elicit T cell responses fail to induce significant antitumor activity, for incompletely understood reasons. We report that radiotherapy upregulates the expression of genes containing immunogenic mutations in a poorly immunogenic mouse model of triple-negative breast cancer. Vaccination with neoepitopes encoded by these genes elicited CD8+ and CD4+ T cells that, whereas ineffective in preventing tumor growth, improved the therapeutic efficacy of radiotherapy. Mechanistically, neoantigen-specific CD8+ T cells preferentially killed irradiated tumor cells. Neoantigen-specific CD4+ T cells were required for the therapeutic efficacy of vaccination and acted by producing Th1 cytokines, killing irradiated tumor cells, and promoting epitope spread. Such a cytotoxic activity relied on the ability of radiation to upregulate class II MHC molecules as well as the death receptors FAS/CD95 and DR5 on the surface of tumor cells. These results provide proof-of-principle evidence that radiotherapy works in concert with neoantigen vaccination to improve tumor control.
Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma ...mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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•Kras/Trp53 mutant tumors lack CD8+ T cells and resist chemo- and immunotherapies•Immunogenic chemotherapy elicits tumor T cell infiltration and controls cancer growth•Tumor control requires CD8+ T cells, TLR4+ cells, and drug actions on cancer cells•T cell influx sensitizes tumors to checkpoint inhibition and durably controls cancer
There is an urgent need to expand the proportion of patients that respond to immune checkpoint therapy. Using clinically relevant genetic mouse models and a combination of immunogenic drugs to trigger T cell infiltration into tumors, Pittet and colleagues are able to make unresponsive tumors sensitive to checkpoint blockade therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Domain wall dynamics in a high magnetostrictive Fe-Co alloy wire (λs = 102 ppm) was evaluated by magnetic Barkhausen noise (MBN) technique.•Stress effect on MBN profiles and the ...frequency analysis were investigated by using a tensile test machine.•The stress dependence of the root mean square (RMS) of the MBN signals shows a good sensitivity (0.038 mV/MPa).
Magnetic Barkhausen noise (MBN) plays significant roles to describe the dynamic of domain walls (DWs), but an in-depth understanding of the correlation between Barkhausen effect and magnetostrictive effect during magnetization process is still limited. In this study, we investigated MBN signals and the frequency spectra in a high-magnetostrictive Fe30Co70 alloy wire (λs = 102 ppm) by evaluating the stress effects on MBN profiles at the stress range of 0–150 MPa using tensile test machine. The results from MBN profiles revealed that MBN in the high magnetic field region was responsible for the localized changes of magnetic flux density, dB/dt induced by magnetic distortion related to non-180° DWs or the magnetization rotation. In MBN spectra, the peak shift towards lower frequencies with the increase of stress indicates that the rough pulse-like MBN outbreaks increase, and it results mainly from the increase of DW jumping length which is caused by the pinning effect at grain boundaries where DW energy is relatively high. In addition, stress dependence of the root mean square (RMS) value of MBN showed a good sensitivity (0.038 mV/MPa). Overall, these findings indicate that new MBN measurement system utilizing magnetostrictive materials can be helpful for a wide range of applications such as mechanical stress sensors and energy harvester systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PT-112 is a novel platinum-pyrophosphate conjugate under clinical development for cancer therapy. PT-112 mediates cytostatic and cytotoxic effects against a variety of human and mouse cancer cell ...lines
. The cytotoxic response to PT-112 is associated with the emission of danger signals underpinning the initiation of anticancer immunity, including calreticulin exposure on the surface of dying cells, as well as ATP and HMGB1 secretion. Consistently, mouse cancer cells succumbing to PT-112
can be used to provide syngeneic, immunocompetent mice with immunological protection against a subsequent challenge with living tumor cells of the same type. Moreover, PT-112 administration synergizes with PD-1 or PD-L1 blockade in the control of mouse cancers in immunologically competent settings, as it simultaneously recruits immune effector cells and depletes immunosuppressive cells in the tumor microenvironment. Finally, PT-112 employed intratumorally in the context of immune checkpoint inhibition initiates a robust immune response that has systemic outreach and limits the growth of untreated, distant lesions. Thus, PT-112 induces the immunogenic demise of cancer cells, and hence stands out as a promising combinatorial partner of immune checkpoint blockers, especially for the treatment of otherwise immunologically cold tumors.
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