GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 8, 2024

Abstract Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and nuclear homology-directed-DNA repair. Here we find GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 fork protection axis. Mechanistically, binds inhibits RAD51 ATPase activity to stabilize on forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases fragments into cytoplasm that activate cGAS–STING pathway trigger pro-inflammatory cytokine production. Moreover syngeneic mouse metastatic ovarian cancer model, depletion context of PARPi reduced tumor burden enabled high survival consistent with immune suppression growth. Collective findings unveil function mechanism BRCA2-RAD51-MRE11 axis suggest as potential therapeutic target an enabling predictive biomarker patient selection immunotherapy combination.

Language: Английский

---

DNA Repair Deficiency Regulates Immunity Response in Cancers: Molecular Mechanism and Approaches for Combining Immunotherapy

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1619 - 1619

Published: March 6, 2023

Defects in DNA repair pathways can lead to genomic instability multiple tumor types, which contributes immunogenicity. Inhibition of damage response (DDR) has been reported increase susceptibility anticancer immunotherapy. However, the interplay between DDR and immune signaling remains unclear. In this review, we will discuss how a deficiency affects anti-tumor immunity, highlighting cGAS-STING axis as an important link. We also review clinical trials that combine inhibition immune-oncology treatments. A better understanding these help exploit cancer immunotherapy improve treatment outcomes for various cancers.

Language: Английский

---

When DNA damage responses meet tumor immunity: From mechanism to therapeutic opportunity

International Journal of Cancer, Journal Year: 2024, Volume and Issue: 155(3), P. 384 - 399

Published: April 24, 2024

DNA damage is a prevalent phenomenon in the context of cancer progression. Evidence suggests that responses (DDR) are pivotal overcoming tumor immune evasion. Alternatively, traditional radiotherapy and chemotherapy operate by inducing damage, consequently stimulating system to target tumors. The intricate interplay between signaling pathways involved DDR activation underscores significance considering both factors developing improved immunotherapies. By delving deeper into mechanisms underlying brought on it becomes possible identify novel treatment approaches boost anticancer response while minimizing undesirable side effects. This review explores behind damage-induced antitumor responses, importance immunity, potential therapeutic for immunotherapy targeting DDR. Additionally, we discuss challenges combination therapy strategies integrating damage-targeting therapies with current immunotherapy. In summary, this highlights critical role immunology, underscoring inhibitors as promising modalities treatment.

Language: Английский

---

The future of cancer treatment: combining radiotherapy with immunotherapy

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: July 9, 2024

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through stimulation of immune response, evidence suggest that combinatorial actions these therapies may augment each other’s beneficial effect complex synergistic mechanisms. These molecular strategies designed to target rapidly dividing cells by either directly or indirectly inducing DNA damage. However, when detect damage, they activate a range signalling pathways known as damage response (DDR) repair. Strategies being developed interfere with DDR in ensure their damage-induced degeneration. The stability cell’s genetic material is largely dependent on efficacy repair therefore, an in-depth understanding damages mechanism(s) important develop promising therapeutic ensuring tumor cell death. In recent years, wide small molecule drugs have been currently employed combat deficiencies associated cells. Sequential concurrent use two modalities significantly enhances anti-tumor however probability increased incidence symptomatic adverse effects. With advent newer IT agents, administration higher doses radiation per fraction, such effects more difficult predict owing paucity randomized trial data. It well established anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed death protein 1(PD-1), anti-Programmed one ligand 1 (PD-L1) can be safely administered RT many studies demonstrated survival benefit combination patients metastatic malignancy. biology radioimmunotherapy (RT/IT) still open area where research need focused determine optimum dosage specially interaction RT/IT dosing schedule. current article we summarised possible intracellular immunological events might triggered combined antagonists highlighted present clinical practices, outcome, toxicity profile this novel strategy.

Language: Английский

---

Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer

Cancer Cell International, Journal Year: 2022, Volume and Issue: 22(1)

Published: Dec. 28, 2022

Abstract Cancer is a heterogeneous disease with multifaceted drug resistance mechanisms (e.g., tumour microenvironment [TME], heterogeneity, and immune evasion). Natural products are interesting repository of bioactive molecules, especially those anticancer activities. Prodigiosin, red pigment produced by Serratia marcescens , possesses inherent characteristics, showing antitumour activities in different cancers breast, gastric) low or without harmful effects on normal cells. The present review discusses the potential role prodigiosin modulating reprogramming metabolism various cells TME, such as T B lymphocytes, tumour-associated macrophages (TAMs), natural killer (NK) cells, dendritic (TADCs), myeloid-derived suppressor (MDSCs) which turn might introduce an immunomodulator cancer therapy.

Language: Английский

---

DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2760 - 2760

Published: Feb. 1, 2023

Head and neck cancer (HNC) is a term collectively used to describe heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, hypopharynx, represents sixth most common type malignancy worldwide. Despite advances multimodality treatment, disease has recurrence rate around 50%, prognosis metastatic patients remains poor. HNCs are characterized by high degree genomic instability, which involves vicious circle accumulating DNA damage, defective damage repair (DDR), replication stress. Nonetheless, induced on tumor cells chemo radiotherapy relies DDR processes for successful response may play an important role development novel more effective therapies. This review summarizes current knowledge genes proteins appear be deregulated pathways, their implication HNC pathogenesis, rationale behind targeting these pathways new We give particular emphasis therapeutic targets have shown promising results at pre-clinical stage those so far been associated with advantage clinical setting.

Language: Английский

---

Review: Protein O-GlcNAcylation regulates DNA damage response: A novel target for cancer therapy

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 264, P. 130351 - 130351

Published: Feb. 24, 2024

Language: Английский

---

Adjudicative efficacy of Bifidobacterium animalis subsp. lactis BLa80 in treating acute diarrhea in children: a randomized, double-blinded, placebo-controlled study

European Journal of Clinical Nutrition, Journal Year: 2024, Volume and Issue: 78(6), P. 501 - 508

Published: March 11, 2024

Abstract The goal of this study is to assess the efficacy and safety Bifidobacterium animalis subsp. lactis BLa80, as an adjunct treatment for diarrhea in children with a randomized, double-blinded, placebo-controlled design. Eligible diarrheal children, aged 0–3 years without need antibiotic based on clinical diagnosis when recruited, were randomized into intervention group (IG, n = 58, probiotic) or control (CG, 53, placebo). primary assessment was duration diarrhea. Fecal samples collected biochemical index measurement, analysis gut microbiome composition, prediction gene family abundances. total IG (122.6 ± 13.1 h) significantly shorter than CG (148.4 17.6 h, p < 0.001). More showed improvements compared CG, both intention-to-treat (81.7% vs. 40.0%, 0.001) per protocol (84.4% vs 45.3%, Cathelicidin level higher that after (4415.00 1036.93 pg/g 3679.49 871.18 pg/g, 0.0175). led increased abundance breve Collinsella aerofaciens species, alpha-diversity ( 0.05), enrichment functional genes microbiota related immunity regulation. Administration BLa80 at dose 5 × 10 9 CFU/day resulted alterations composition functions.

Language: Английский

---

Recent Advances in Immunotherapy for Advanced Biliary Tract Cancer

Current Treatment Options in Oncology, Journal Year: 2024, Volume and Issue: 25(8), P. 1089 - 1111

Published: July 27, 2024

Opinion Statement Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium biliary tract. Most patients present with locally advanced or metastatic disease at time diagnosis. For unresectable BTC, survival advantage provided by systemic chemotherapy was limited. Over last decade, immunotherapy has significantly improved therapeutic landscape solid tumors. There an increasing number studies evaluating application in including immune checkpoint inhibitors (ICIs), vaccines and adoptive cell therapy. The limited response to ICIs monotherapy unselected prompted investigators explore different combination therapy strategies. Early clinical trials vaccination have shown encouraging results. However, there still been long way go via validation efficacy exploration strategies increase efficacy. Identifying biomarkers predict will allow more accurate selection candidates. This review provide up-to-date overview current data on role immunotherapy, summarize promising predictive discuss perspective for future research direction BTC.

Language: Английский

---

Anti-cancer immune responses to DNA damage response inhibitors: Molecular mechanisms and progress toward clinical translation

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Oct. 6, 2022

DNA damage response inhibitors are widely used anti-cancer agents that have potent activity against tumor cells with deficiencies in various proteins such as BRCA1/2. Inhibition of other this pathway including PARP, DNA-PK, WEE1, CHK1/2, ATR, or ATM can sensitize cancer to radiotherapy and chemotherapy, combinations currently being tested clinical trials for treatment many malignancies breast, ovarian, rectal, lung cancer. Unrepaired induced by alone combination radio- chemotherapy has a direct cytotoxic effect on also engage innate adaptive immune responses. damage-induced stimulation occurs variety mechanisms the cGAS/STING pathway, STAT1 downstream TRAIL activation, cell activation. Whether not relative contribution these varies after different across cancers genetic aberrations enzymes is well-characterized, limiting design optimal chemotherapy. Here, we review how inhibition key induces responses radiotherapy, and/or immunotherapy. We discuss current progress translation immunostimulatory DNA-damaging regimens necessary future directions optimize immune-sensitizing potential inhibitors.

Language: Английский

---