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Nature Communications May 2024Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as...
Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80 I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.
Topics: Extracellular Vesicles; Programmed Cell Death 1 Receptor; Humans; B7-1 Antigen; B7-H1 Antigen; Animals; Mice; Cell Line, Tumor; Female; Neoplasms; Immune Checkpoint Inhibitors; Immune Tolerance; Mice, Inbred C57BL; Male; Tumor Microenvironment
PubMed: 38719909
DOI: 10.1038/s41467-024-48200-9 -
Journal of Radiation Research May 2024Lymphocytes, which are highly sensitive to radiation, play a crucial role in the body's defense against tumors. Radiation-induced lymphopenia has been associated with...
Lymphocytes, which are highly sensitive to radiation, play a crucial role in the body's defense against tumors. Radiation-induced lymphopenia has been associated with poorer outcomes in different cancer types. Despite being the largest secondary lymphoid organ, the spleen has not been officially designated as an organ at risk. This study hypothesizes a connection between spleen irradiation and lymphopenia and seeks to establish evidence-based dosage limits for the spleen. We retrospectively analyzed data from 96 patients with locally advanced gastric cancer who received postoperative chemoradiotherapy (CRT) between May 2010 and May 2017. Complete blood counts were collected before, during and after CRT. We established a model for predicting the minimum absolute lymphocyte count (Min ALC) and to investigate potential associations between spleen dosimetric variables and Min ALC. The median follow-up was 60 months. The 5-year overall survival (OS) and disease-free survival (DFS) were 65.2% and 56.8%, respectively. The median values of pre-treatment ALC, Min ALC and post-treatment ALC were 1.40 × 109, 0.23 × 109 and 0.28 × 109/L, respectively. Regression analysis confirmed that the primary tumor location, number of fractions and spleen V5 were significant predictors of Min ALC during radiation therapy. Changes in ALC (ΔALC) were identified as an independent predictor of both OS and DFS. Spleen V5 is an independent predictor for Min ALC, and the maximum dose of the spleen is associated with an increased risk of severe lymphopenia. Therefore, these doses should be restricted in clinical practice. Additionally, ΔALC can serve as a prognostic indicator for adjuvant radiotherapy in gastric cancer.
Topics: Humans; Lymphopenia; Male; Female; Middle Aged; Spleen; Aged; Stomach Neoplasms; Adult; Dose-Response Relationship, Radiation; Lymphocyte Count; Disease-Free Survival; Retrospective Studies; Chemoradiotherapy; Radiotherapy Dosage; Aged, 80 and over
PubMed: 38718391
DOI: 10.1093/jrr/rrae023 -
Cancer Letters Jul 2024Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study...
Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study examines the role of lymphocyte immunoglobulin-like receptor B2 (LILRB2) in modulating RT-induced senescence and radiosensitivity in NSCLC. Through methodologies including irradiation, lentivirus transfection, and various molecular assays, we assessed LILRB2's expression and its impact on cellular senescence levels and tumor cell behaviors. Our findings reveal that RT upregulates LILRB2, facilitating senescence and a senescence-associated secretory phenotype (SASP), which in turn enhances tumor proliferation and resistance to radiation. Importantly, LILRB2 silencing attenuates these effects by inhibiting the JAK2/STAT3 pathway, significantly increasing radiosensitivity in NSCLC models. Clinical data correlate high LILRB2 expression with reduced RT response and poorer prognosis, suggesting LILRB2's pivotal role in RT-induced senescence and its potential as a therapeutic target to improve NSCLC radiosensitivity.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cellular Senescence; Radiation Tolerance; Lung Neoplasms; Receptors, Immunologic; Cell Line, Tumor; Cell Proliferation; Membrane Glycoproteins; STAT3 Transcription Factor; Animals; Janus Kinase 2; Mice; Signal Transduction; Gene Expression Regulation, Neoplastic; Senescence-Associated Secretory Phenotype; A549 Cells; Female
PubMed: 38705566
DOI: 10.1016/j.canlet.2024.216930 -
Microbiology Spectrum Jun 2024We investigated the impact of various complex organic nitrogen sources on the submerged liquid fermentation of , a versatile entomopathogenic fungus known for producing...
UNLABELLED
We investigated the impact of various complex organic nitrogen sources on the submerged liquid fermentation of , a versatile entomopathogenic fungus known for producing hydrophilic yeast-like single cells called blastospores. Specifically, we examined yeast extract, autolyzed yeast, inactive yeast, cottonseed flour, corn bran, and corn gluten meal as nitrogen compounds with different carbon-to-nitrogen (C:N) ratios. Our comprehensive analysis encompassed blastospore production, tolerance to abiotic stresses, shelf stability after drying, and virulence against mealworm larvae, crucial attributes for developing effective blastospore-based biopesticides. Notably, cottonseed flour emerged as the optimal nitrogen source, yielding up to 2.5 × 10 blastospores/mL within 3 days in a bioreactor. These blastospores exhibited the highest tolerance to heat stress and UV-B radiation exposure. The endogenous C:N ratio in blastospore composition was also impacted by nitrogen sources. Bioassays with mealworm larvae demonstrated that blastospores from cottonseed flour were the most virulent, achieving faster lethality (lower LT) and requiring a lower inoculum (LC). Importantly, blastospores produced with cottonseed flour displayed extended viability during storage, surpassing the retention of viability compared to those from autolyzed yeast over 180 days at 4°C. Despite differences in storage viability, both nitrogen sources conferred similar long-term blastospore bioactivity against mealworms. In summary, this research advances our understanding of the crucial impact of complex organic nitrogen selection on the phenotypic traits of blastospores in association with their intracellular C:N ratio, contributing to the production of ecologically fit, shelf-stable, and virulent propagules for effective pest biocontrol programs.
IMPORTANCE
Biological control through entomopathogenic fungi provides essential ecological services in the integrated management of agricultural pests. In the context of submerged liquid fermentation, the nutritional composition significantly influences the ecological fitness, virulence and quality of these fungi. This study specifically explores the impact of various complex organic nitrogen sources derived from agro-industrial byproducts on the submerged liquid fermentation of , a versatile entomopathogenic fungus known for producing hydrophilic yeast-like blastospores. Notably, manipulating the nitrogen source during submerged cultivation can influence the quality, fitness, and performance of blastospores. This research identifies cottonseed flour as the optimal low-cost nitrogen source, contributing to increased production yields, enhanced multi-stress tolerance, heightened virulence with extended shelf life and long-term bioactivity. These findings deepen our understanding of the critical role of nitrogen compound selection in liquid media formulation, facilitating the production of ecologically fit and virulent blastospores for more effective pest biocontrol programs.
Topics: Beauveria; Nitrogen; Virulence; Spores, Fungal; Animals; Stress, Physiological; Larva; Fermentation; Agriculture; Industrial Waste
PubMed: 38700331
DOI: 10.1128/spectrum.04040-23 -
Journal of Cancer Research and Clinical... May 2024High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to... (Review)
Review
High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to induce complex and clustered DNA lesions. However, the development of radiation resistance poses a significant barrier. The potential molecular mechanisms that could confer resistance development are translesion synthesis (TLS), replication gap suppression (RGS) mechanisms, autophagy, epithelial-mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes. This article will discuss various types of complex clustered DNA damage, their repair mechanisms, mutagenic potential, and the development of radiation resistance strategies. Furthermore, it highlights the importance of careful consideration and patient selection when employing high-LET radiotherapy in clinical settings.
Topics: Humans; Neoplasms; Radiation Tolerance; Linear Energy Transfer; DNA Damage; DNA Repair; Animals
PubMed: 38696003
DOI: 10.1007/s00432-024-05757-8 -
International Journal of Molecular... Jun 2024Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on...
Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low‑dose radiation‑sensitive markers. The HuT 78 and IM‑9 cell lines were irradiated in a concentration‑dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration‑dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an model was employed using sub‑lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub‑lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML‑277, pifithrin‑α, and nutlin‑3a were evaluated for their ability to modulate radiation‑induced cell death. The use of BML‑277 led to a decrease in radiation‑induced p‑CHK2 and γH2AX levels and mitigated radiation‑induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation‑sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.
Topics: DNA Damage; Humans; Animals; Radiation, Ionizing; Signal Transduction; Ataxia Telangiectasia Mutated Proteins; Mice; Checkpoint Kinase 2; Histones; Tumor Suppressor Protein p53; Male; Imidazoles; Radiation-Protective Agents; Cell Line, Tumor; Dose-Response Relationship, Radiation
PubMed: 38695243
DOI: 10.3892/ijmm.2024.5380 -
Experimental & Molecular Medicine May 2024Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational...
Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1; Sftpa1-Cre mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1; Sftpa1-Cre mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.
Topics: Animals; Biopterins; Reactive Oxygen Species; Mice; Lung Injury; GTP Cyclohydrolase; Humans; Radiation Tolerance; Lactate Dehydrogenase 5; Mice, Knockout; Nitric Oxide; L-Lactate Dehydrogenase; Protein Processing, Post-Translational; Radiation, Ionizing
PubMed: 38689083
DOI: 10.1038/s12276-024-01208-z -
Acta Medica Okayama Apr 2024Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities...
Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.
Topics: Sarcoma; Humans; Oncolytic Virotherapy; bcl-X Protein; Radiation Tolerance; Cell Line, Tumor; Animals; Tumor Suppressor Protein p53; Mice; Apoptosis; Adenoviridae
PubMed: 38688833
DOI: 10.18926/AMO/66924 -
Journal of Cancer Research and... Apr 2024Tumor-associated macrophages (TAMs) are intimately involved in cancer radiochemotherapy resistance. However, the mechanism by which macrophages affect radiosensitivity...
BACKGROUND
Tumor-associated macrophages (TAMs) are intimately involved in cancer radiochemotherapy resistance. However, the mechanism by which macrophages affect radiosensitivity through autophagy remains unclear. The purpose of our study was to investigate how activating autophagy in type-II macrophages (M2) by using rapamycin (RAP) would affect the radiosensitivity of colorectal cancer (CRC) xenografts.
MATERIALS AND METHODS
A nude mouse CRC model was established by injecting LoVo CRC cells. After tumor formation, supernatant from M2 cells (autophagy-unactivated), autophagy-activated M2 cells, or autophagy-downregulated M2 cells was injected peritumorally. All tumor-bearing mice were irradiated with 8-Gy X-rays twice, and the radiosensitivity of CRC xenografts was analyzed in each group.
RESULTS
The mass, volume, and microvessel density (MVD) of tumors in the autophagy-unactivated M2 group significantly increased; however, supernatant from M2 cells that were autophagy-activated by rapamycin significantly decreased tumor weight, volume, and MVD compared with negative control. Combining bafilomycin A1 (BAF-A1) with RAP treatment restored the ability of the M2 supernatant to increase tumor mass, volume, and MVD. Immunohistochemical and Western blot results showed that compared with the negative control group, supernatant from M2 cells that were not activated by autophagy downregulated the expression of Livin and Survivin in tumor tissues; activation of M2 autophagy further downregulated the protein levels.
CONCLUSIONS
Therefore, autophagy-activated M2 supernatant can downregulate the expression of the antiapoptotic genes Livin and Survivin in CRC xenografts, improving the radiosensitivity of CRC by inducing apoptosis in combination with radiotherapy and inhibiting the growth of transplanted tumors.
Topics: Animals; Colorectal Neoplasms; Mice; Autophagy; Humans; Radiation Tolerance; Sirolimus; Xenograft Model Antitumor Assays; Mice, Nude; Cell Line, Tumor; Apoptosis; Tumor-Associated Macrophages; Survivin; Mice, Inbred BALB C; Male
PubMed: 38687942
DOI: 10.4103/jcrt.jcrt_215_23 -
Journal of Cancer Research and... Apr 2024Radiotherapy (RT) plays an important role in esophageal cancer (EC) patients aged ≥80 years. However, the survival modality and prognostic factors remain poorly...
PURPOSE
Radiotherapy (RT) plays an important role in esophageal cancer (EC) patients aged ≥80 years. However, the survival modality and prognostic factors remain poorly understood. Thus, this study aimed to evaluate the tolerance and long-term overall survival (OS) of patients aged ≥80 years who were diagnosed with EC and underwent definitive RT.
MATERIALS AND METHODS
A total of 213 consecutive patients with EC over 80 years old who were treated with curative intent RT between February 1999 and December 2015 at our institution were retrospectively reviewed. The clinical prognostic variables were analyzed against OS in univariate analyses using log-rank tests and in a multivariate model using Cox regression proportional hazards analysis.
RESULT
The median patient age was 82 (range: 80-94) years. Atotal of 192 patients (90.1%) completed the definitive RT (median: 60 Gy, range: 50-72 Gy), and 11 patients had grade 4 or higher acute toxicity, including esophagitis, a cardiac event, infections, and sudden death. Atotal of 168 deaths (78.9%) were observed with a median follow up of 47 months (range: 0-153 months). The OS rates were 50.3%, 17.6%, and 13.2% at 1, 3, and 5 years, respectively. Multivariable analysis identified that tumors located in the cervical and upper thorax, a shorter tumor lesion, RT treatment of 50-60Gy, and a better response to treatment were the factors associated with longer OS.
CONCLUSION
Definitive RT could be considered as an effective treatment for patients with EC who are older than 80 years, and 50-60 Gy seems to be a reasonable dose for these patients.
Topics: Humans; Esophageal Neoplasms; Female; Male; Aged, 80 and over; Retrospective Studies; Prognosis; Treatment Outcome; Radiotherapy Dosage; Neoplasm Staging; Survival Rate; Follow-Up Studies
PubMed: 38687940
DOI: 10.4103/jcrt.jcrt_833_22