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2.
Angew Chem Int Ed Engl ; : e202417027, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39375150

RESUMO

The activation of the stimulator of interferon genes (STING) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. However, synthetic STING agonists like 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (MSA-2) exhibit suboptimal pharmacokinetics and fail to sustain STING activation in tumors for effective antitumor responses. Here, we report the design of MOF/MSA-2, a bifunctional MSA-2 conjugated nanoscale metal-organic framework (MOF) based on Hf6 secondary building units (SBUs) and hexakis(4'-carboxy[1,1'-biphenyl]-4-yl)benzene bridging ligands, for potent cancer radio-immunotherapy. By leveraging the high-Z properties of the Hf6 SBUs, the MOF enhances the therapeutic effect of X-ray radiation and elicits potent immune stimulation in the tumor microenvironment. MOF/MSA-2 further enhances radiotherapeutic effects of X-rays by enabling sustained STING activation and promoting the infiltration and activation of immune cells in the tumors. MOF/MSA-2 plus low-dose X-ray irradiation elicits strong STING activation and potent tumor regression, and when combined with an immune checkpoint inhibitor, effectively suppresses both primary and distant tumors through systemic immune activation.

3.
J Clin Invest ; 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39325547

RESUMO

RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from cancer patients, but not in other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.

4.
Adv Mater ; : e2405494, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39252688

RESUMO

The efficacy of radiotherapy (RT) is limited by inefficient X-ray absorption and reactive oxygen species generation, upregulation of immunosuppressive factors, and a reducing tumor microenvironment (TME). Here, the design of a mitochondria-targeted and digitonin (Dig)-loaded nanoscale metal-organic framework, Th-Ir-DBB/Dig, is reported to overcome these limitations and elicit strong antitumor effects upon low-dose X-ray irradiation. Built from Th6O4(OH)4 secondary building units (SBUs) and photosensitizing Ir(DBB)(ppy)2 2+ (Ir-DBB, DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; ppy = 2-phenylpyridine) ligands, Th-Ir-DBB exhibits strong RT-radiodynamic therapy (RDT) effects via potent radiosensitization with high-Z SBUs for hydroxyl radical generation and efficient excitation of Ir-DBB ligands for singlet oxygen production. Th-Ir-DBB/Dig releases digitonin in acidic TMEs to trigger disulfidptosis of cancer cells and sensitize cancer cells to RT-RDT through glucose and glutathione depletion. The released digitonin simultaneously downregulates multiple immune checkpoints in cancer cells and T cells through cholesterol depletion. As a result, Th-Ir-DBB/dig plus X-ray irradiation induces strong antitumor immunity to effectively inhibit tumor growth in mouse models of colon and breast cancer.

5.
Lancet Oncol ; 25(8): e352-e362, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39089313

RESUMO

Radiotherapy exerts immunostimulatory and immunosuppressive effects, both locally, within the irradiated tumour microenvironment, and systemically, outside the radiation field. Inspired by preclinical data that showed synergy between radiotherapy and immune checkpoint inhibitors, multiple clinical trials were initiated with the hypothesis that combined treatment with radiotherapy and immune checkpoint inhibitors could stimulate a robust systemic immune response and improve clinical outcomes. However, despite early optimism, radioimmunotherapy trials in the curative and metastatic settings have met with little success. In this Review, we summarise the immunostimulatory effects of radiotherapy that provided the theoretical basis for trials of combination radiotherapy and immune checkpoint inhibitors. We also discuss findings from clinical trials incorporating radiotherapy and immune checkpoint inhibitors and examine the success of these trials in the context of the immunosuppressive effects of radiotherapy. We conclude by highlighting targets for relieving radiotherapy-induced immunosuppression with the goal of enhancing the combined effects of radiotherapy and immune checkpoint inhibitors.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Microambiente Tumoral , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/imunologia , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Animais , Radioimunoterapia , Terapia Combinada
6.
Angew Chem Int Ed Engl ; : e202412844, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39146242

RESUMO

Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.

7.
Adv Sci (Weinh) ; 11(35): e2403520, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39013093

RESUMO

The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria-targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5-carboxy-8-hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death-1 (PD-L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD-L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple-negative breast cancer in mouse models without causing obvious side effects.


Assuntos
Cobre , Modelos Animais de Doenças , Regulação para Baixo , Imunoterapia , Mitocôndrias , Nanopartículas , Animais , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Imunoterapia/métodos , Nanopartículas/química , Regulação para Baixo/efeitos dos fármacos , Cobre/metabolismo , Cobre/química , Cobre/farmacologia , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Feminino , Linhagem Celular Tumoral , Inibidores de Checkpoint Imunológico/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia
9.
Sci Adv ; 10(29): eado0082, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39018400

RESUMO

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.


Assuntos
Proteínas de Membrana , Animais , Proteínas de Membrana/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Oxaliplatina/farmacologia , Oxaliplatina/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Nucleotídeos Cíclicos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Am Chem Soc ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837955

RESUMO

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

11.
Clin Cancer Res ; 30(19): 4450-4463, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691100

RESUMO

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT but also associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy. See related commentary by Kalinski et al., p. 4260.


Assuntos
Quimiocina CCL22 , Células Dendríticas , Linfócitos T Reguladores , Animais , Células Dendríticas/imunologia , Quimiocina CCL22/metabolismo , Quimiocina CCL22/genética , Camundongos , Linfócitos T Reguladores/imunologia , Humanos , Tolerância a Radiação , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Receptores ErbB/antagonistas & inibidores , Neoplasias/imunologia , Neoplasias/radioterapia , Neoplasias/patologia , Feminino , Modelos Animais de Doenças
12.
J Exp Med ; 221(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38771260

RESUMO

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.


Assuntos
Neoplasias , Radioterapia , Microambiente Tumoral , Humanos , Neoplasias/radioterapia , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Animais , Radioterapia/métodos , Imunidade Inata/efeitos da radiação , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Imunidade Adaptativa
13.
Adv Sci (Weinh) ; 11(23): e2310309, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38477411

RESUMO

The recent discovery of copper-mediated and mitochondrion-dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer therapy. Here the design of a core-shell nanoparticle, CuP/Er, for the co-delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis is reported. The anti-Warburg effect of Er sensitizes tumor cells to Cu-mediated cuproptosis, leading to irreparable mitochondrial damage by depleting glutathione and enhancing lipid peroxidation. CuP/Er induces strong immunogenic cell death, enhances antigen presentation, and upregulates programmed death-ligand 1 expression. Consequently, CuP/Er promotes proliferation and infiltration of T cells, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple-negative breast cancer and prevent tumor metastasis. This study suggests a unique opportunity to synergize cuproptosis and ferroptosis with combination therapy nanoparticles to elicit strong antitumor effects and potentiate current cancer immunotherapies.


Assuntos
Cobre , Ferroptose , Imunoterapia , Nanopartículas , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Imunoterapia/métodos , Modelos Animais de Doenças , Humanos , Linhagem Celular Tumoral , Feminino , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Piperazinas
14.
Clin Cancer Res ; 30(9): 1945-1958, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427437

RESUMO

PURPOSE: Radiotherapy (RT) is a widely employed anticancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. The purpose of this study is to investigate immune suppressive factors of radiotherapy. EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated. RESULTS: Through analysis of PD-L1 expression and myeloid-derived suppressor cells (MDSC) frequencies using patient peripheral blood mononuclear cells and murine two-tumor and metastasis models, we report that local irradiation can induce a systemic increase in MDSC, as well as PD-L1 expression on dendritic cells and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, nonirradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSC can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT. CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during irradiation can enhance abscopal tumor control and reduce metastasis.


Assuntos
Antígeno B7-H1 , Células Supressoras Mieloides , Animais , Antígeno B7-H1/metabolismo , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Humanos , Metástase Neoplásica , Linhagem Celular Tumoral , Feminino , Modelos Animais de Doenças , Quimiocina CXCL10/metabolismo
15.
Eur J Cancer ; 201: 113972, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430868

RESUMO

It remains highly unclear and debatable whether combining radiotherapy (RT) and immune checkpoint blocker (ICB) therapy yields improved outcomes compared to either modality alone. Whereas some randomized data have shown improved outcomes, others have not. As a result of these conflicting data, it is essential to reconcile differences in the data and postulate reasons thereof. This work seeks to address these discrepancies, and uses the lessons learned from both positive and negative trials, including the most cutting-edge data available, in order to guide future clinical trial design and clarify the ideal/expected role of combinatorial therapy going forward. Because RT offers two distinct contributions (cytoreductive (local) effects & immune-stimulating (systemic) effects), RT should complement immunotherapy by addressing immunotherapy-resistant clones, and immunotherapy should complement RT by addressing RT-resistant or out-of-field clones. RT is not merely a single "drug", but rather a constellation of diverse "drugs" that can be varied based on dose regimens, previous systemic therapy regimens, number of irradiated sites, treatment intent/location/timing, tumor biology, and individual patient immunological circumstances. These factors are discussed as an important explanation for the discrepancies in results of various randomized trials in heterogeneous populations and clinical settings, and these discrepancies may continue until trials of more uniform circumstances are designed to use particular RT paradigms that meaningfully add value to systemic therapy.


Assuntos
Imunoterapia , Radiocirurgia , Humanos , Terapia Combinada , Imunoterapia/métodos , Radiocirurgia/métodos
16.
ACS Nano ; 18(6): 5152-5166, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38286035

RESUMO

Blockade of programmed cell death-1/programmed cell death-ligand 1 (PD-L1) immune checkpoints with monoclonal antibodies has shown great promise for cancer treatment, but these antibodies can cause immune-related adverse events in normal organs. Here we report a dual-cell targeted chemo-immunotherapeutic nanoscale coordination polymer (NCP), OxPt/BP, comprising oxaliplatin (OxPt) and 2-bromopalmitic acid (BP), for effective downregulation of PD-L1 expression in both cancer cells and dendritic cells (DCs) by inhibiting palmitoyl acyltransferase DHHC3. OxPt/BP efficiently promotes DC maturation by increasing intracellular oxidative stress and enhancing OxPt-induced immunostimulatory immunogenic cancer cell death. Systemic administration of OxPt/BP reduces the growth of subcutaneous and orthotopic colorectal carcinoma by facilitating the infiltration and activation of cytotoxic T lymphocytes together with reducing the population of immunosuppressive regulatory T cells. As a result, OxPt/BP significantly extends mouse survival without causing side effects. This work highlights the potential of NCPs in simultaneously reprogramming cancer cells and DCs for potent cancer treatment.


Assuntos
Antígeno B7-H1 , Neoplasias , Animais , Camundongos , Ligantes , Neoplasias/tratamento farmacológico , Imunoterapia , Imunidade Adaptativa , Apoptose , Células Dendríticas , Linhagem Celular Tumoral
17.
J Am Chem Soc ; 146(1): 849-857, 2024 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-38134050

RESUMO

Phthalocyanine photosensitizers (PSs) have shown promise in fluorescence imaging and photodynamic therapy (PDT) of malignant tumors, but their practical application is limited by the aggregation-induced quenching (AIQ) and inherent photobleaching of PSs. Herein, we report the synthesis of a two-dimensional nanoscale covalent organic framework (nCOF) with staggered (AB) stacking of zinc-phthalocyanines (ZnPc), ZnPc-PI, for fluorescence imaging and mitochondria-targeted PDT. ZnPc-PI isolates and confines ZnPc PSs in the rigid nCOF to reduce AIQ, improve photostability, enhance cellular uptake, and increase the level of reactive oxygen species (ROS) generation via mitochondrial targeting. ZnPc-PI shows efficient tumor accumulation, which allowed precise tumor imaging and nanoparticle tracking. With high cellular uptake and tumor accumulation, intrinsic mitochondrial targeting, and enhanced ROS generation, ZnPc-PI exhibits potent PDT efficacy with >95% tumor growth inhibition on two murine colon cancer models without causing side effects.


Assuntos
Estruturas Metalorgânicas , Neoplasias , Compostos Organometálicos , Fotoquimioterapia , Compostos de Zinco , Camundongos , Humanos , Animais , Fotoquimioterapia/métodos , Estruturas Metalorgânicas/uso terapêutico , Espécies Reativas de Oxigênio , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Isoindóis , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Mitocôndrias , Linhagem Celular Tumoral
18.
Med ; 4(12): 863-874, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38070481

RESUMO

Emerging evidence suggests that local tumor radiotherapy reshapes the repertoire of circulating myeloid-derived suppressor cells (MDSCs) and leads to their infiltration into the tumor microenvironment, which poses a major obstacle for radiotherapy efficacy. Recent findings have identified RNA m6A modification at the nexus of both anti-tumor immunity and radiation response. Here, we examine the mechanisms by which this RNA modification modulates the immune milieu of the radiation-remodeled tumor microenvironment. We discuss potential therapeutic interventions targeting m6A machinery to improve radiotherapy response.


Assuntos
Células Supressoras Mieloides , Neoplasias , Humanos , Células Supressoras Mieloides/patologia , RNA , Neoplasias/genética , Neoplasias/radioterapia , Metilação , Microambiente Tumoral/genética
20.
Front Med (Lausanne) ; 10: 1269689, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37904839

RESUMO

Background: Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Materials and methods: Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. Results: An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. Conclusion: This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

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