Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Авг. 19, 2023

Abstract Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote release cytokines and chemokines, triggers inflammatory reactions changes tumor microenvironment (TME), thereby inhibiting immune function causing invasion metastasis Radioresistance major disease progression cancer, it associated heterogeneity. Therefore, a better understanding radioresistance mechanisms may generate reversal strategies to improve cure rates survival periods ESCC patients. We mainly summarized possible order reveal new targets therapy. Then we compared current reverse radioresistance.

Язык: Английский

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Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma

Cancer Cell, Год журнала: 2023, Номер 41(11), С. 1852 - 1870.e9

Опубликована: Окт. 12, 2023

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays progenitor (Tpex) phenotype and correlates complete response to ICB. We validate Tex-SPRY1 as an ICB-specific predictor improved survival using independent ICB-/non-ICB cohorts demonstrate expression enforces Tpex enhances ICB efficacy. Additionally, contribute proinflammatory macrophages functional state B cells, which thereby promotes antitumor immunity by enhancing effector functions. Overall, our findings unravel progenitor-like cells' role effective responses for inform mechanistic biomarkers future individualized immunotherapy.

Язык: Английский

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Advances in diagnosis and management of cancer of the esophagus

BMJ, Год журнала: 2024, Номер unknown, С. e074962 - e074962

Опубликована: Июнь 3, 2024

Abstract Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These are esophageal adenocarcinoma (EAC) squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, patients presenting late stage disease.2 Novel strategies to improve early detection respective precursor lesions, dysplasia, Barrett’s esophagus offer potential outcomes. The introduction a limited number biologic agents, as well immune checkpoint inhibitors, resulting in improvements systemic treatment locally advanced metastatic cancer. developments, coupled minimally invasive surgical endoscopic approaches, adaptive precision radiotherapy technologies, outcomes still further. This review summarizes latest advances diagnosis management cancer, developments understanding biology this disease.

Язык: Английский

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Recent developments in immunotherapy for gastrointestinal tract cancers

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Авг. 9, 2024

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. role immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in treatment advanced perioperative GI Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen unselected gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), esophageal (EC). In addition, encouraging performance claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy later-line cancers brings new hope cell solid tumour treatment. Nevertheless, remains yet precise, researchers are dedicated to further maximising optimising efficacy. This review summarises important research, latest progress, future directions including EC, G/GEJC, CRC.

Язык: Английский

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Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Янв. 18, 2025

Clinically, multimodal therapies are adopted worldwide for the management of cancer, which continues to be a leading cause death. In recent years, immunotherapy has firmly established itself as new paradigm in cancer care that activates body's immune defense cope with cancer. Immunotherapy resulted significant breakthroughs treatment stubborn tumors, dramatically improving clinical outcome patients. Multiple forms immunotherapy, including checkpoint inhibitors (ICIs), adoptive cell therapy and vaccines, have become widely available. However, effectiveness these immunotherapies is not much satisfying. Many patients do respond disease recurrence appears unavoidable because rapidly evolving resistance. Moreover, can give rise severe off-target immune-related adverse events. Strategies remove hindrances mainly focus on development combinatorial or exploitation novel immunotherapeutic mediations. Nanomaterials carrying anticancer agents target site considered practical approaches treatment. Nanomedicine combined offers possibility potentiate systemic antitumor immunity facilitate selective cytotoxicity against cells an effective safe manner. A myriad nano-enabled currently under investigation. Owing gaps between preclinical studies, nano-immunotherapy faces multiple challenges, biosafety nanomaterials trial design. this review, we provide overview summarize evidence indicating how nanomedicine-based increase efficacy immunotherapies. We also discuss key challenges emerged era nanotechnology-based immunotherapy. Taken together, combination drawing increasing attention, it anticipated will achieve desired success therapy.

Язык: Английский

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Perioperative outcomes of neoadjuvant chemotherapy plus camrelizumab compared with chemotherapy alone and chemoradiotherapy for locally advanced esophageal squamous cell cancer

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Фев. 7, 2023

Purpose Neoadjuvant chemoimmunotherapy (nCIT) is becoming a new therapeutic frontier for resectable esophageal squamous cell carcinoma (ESCC); however, crucial details and technical know-how regarding surgical techniques the perioperative challenges following nCIT remain poorly understood. The study investigated compared advantages disadvantages of esophagectomy with neoadjuvant chemotherapy (nCT) chemoradiotherapy (nCRT). Methods We retrospectively analyzed data patients initially diagnosed ESCC at clinical stage T2-4N+ received therapy followed by Hunan Cancer Hospital between October 2014 February 2021. Patients were divided into three groups according to treatment: (i) nCIT; (ii) nCT; (iii) nCRT. Results There 34 in group, 97 nCT 31 nCRT group. Compared nCT, achieved higher pathological complete response (pCR; 29.0% versus 4.1%, p<0.001) major (MPR; 52.9% 16.5%, rates, more resected lymph nodes during surgery (25.06 ± 7.62 20.64 9.68, p =0.009), less intraoperative blood loss (200.00 73.86 266.49 176.29 mL, =0.035), comparable results other parameters. nCRT, similar pCR (29.0% 25.8%) MPR (52.9% 51.6%, p=0.862) significantly 16.94 7.24, p<0.001), shorter operation time (267.79 50.67 306.32 79.92 min, =0.022), 264.53 139.76 fewer ICU admissions after (29.4% 80.6%, p<0.001). Regarding adverse events complications, no significant statistical differences detected or groups. 3-year overall survival rate was 73.3%, slightly than 46.1% 39.7% statistically (p=0.883). Conclusions This analysis showed that safe feasible, satisfactory rates. Esophagectomy has several over morbidity mortality. long-term benefits still requires further investigation.

Язык: Английский

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Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial

EClinicalMedicine, Год журнала: 2024, Номер 69, С. 102471 - 102471

Опубликована: Фев. 6, 2024

BackgroundConcurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence still main failure pattern, accounting more than half of all failures, indicating that sensitivity radiotherapy needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by could promote tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity improve control.MethodsWe did a multicenter, single-arm, phase 2 in China. Patients with cancer were enrolled this study. In induction phase, patients received two cycles sintilimab, paclitaxel carboplatin once per 21 days. concurrent treated five week 50.4Gy delivered 28 fractions. The primary endpoint was 2-year control rate. Hypoxia vessel normalization assessed before after using immunofluorescence perfusion CT. registered ClinicalTrials.gov (NCT03985046).FindingsSeventy-five study between October 2019 April 2021. median follow-up surviving 33.6 months (IQR 29.3–35.7). rate 81.7% (95% confidence interval, 72.7%–90.7%), which much higher chemoradiation only (71.3%) previous studies. Vascular hypoxia alleviation observed both biopsy specimens CT.InterpretationThe addition immunotherapy as non-surgical treatment. New combination led through promoting alleviating hypoxia. Our findings suggest potential option future treatment.FundingNational Natural Science Foundation China Shanghai Rising-Star Program.

Язык: Английский

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Immunotherapy for esophageal cancer: Where are we now and where can we go

World Journal of Gastroenterology, Год журнала: 2024, Номер 30(19), С. 2496 - 2501

Опубликована: Май 17, 2024

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis, and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma (ESCC) past decade. Monoclonal antibodies that selectively inhibit programmed death-1 (PD-1) activity now become standard of care ESCC metastatic settings, a high expectation to provide clinical benefit during perioperative period. Further, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody also been approved recurrent/metastatic combination with anti-PD-1 antibody. Well understanding existing evidence immune-based treatments for ESCC, as well recent trials on combinations chemotherapy different settings neoadjuvant, adjuvant, diseases, may future prospects better outcomes.

Язык: Английский

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Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma

Genome Medicine, Год журнала: 2024, Номер 16(1)

Опубликована: Апрель 2, 2024

Abstract Background The efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within tumor microenvironment (TME). Unveiling immune landscape ESCC context NAT could shed light on heterogeneity and optimize therapeutic strategies for patients. Methods We analyzed single cells from 22 baseline 24 post-NAT treatment samples stage II/III patients to explore association between pathological response anti-PD-1 combination therapy, including complete (pCR), major (MPR), incomplete (IPR). Results Single-cell profiling identified 14 subsets cancer, immune, stromal cells. Trajectory analysis unveiled an interesting link cancer differentiation NAT. tumors enriched with less differentiated exhibited a potentially favorable NAT, while clusters more may resist treatment. Deconvolution transcriptomes pre-treatment gene signatures contributed specific populations. Upregulated genes associated better responses CD8 + effector T primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, negative regulation apoptotic process, whereas downregulated were dominated those response-activating surface receptor signaling pathway. Natural killer pCR showed similar upregulation expression IFNγ but downregulation neutrophil-mediated immunity pathways. A decreased cellular contexture regulatory TME indicated Cell–cell communication revealed extensive interactions CCL5 its CCR5 various tumors. Immune checkpoint interaction pairs, CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, TNFSF4-TNFRSF4, might serve as additional targets ICI therapy ESCC. Conclusions This pioneering study intriguing patients, revealing distinct subgroups which be effective. also delineated clinical provides insights understanding how respond further identifying novel future.

Язык: Английский

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Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 22, 2024

Neoadjuvant immunochemotherapy (nICT) has dramatically changed the treatment landscape of operable esophageal squamous cell carcinoma (ESCC), but factors influencing tumor response to nICT are not well understood. Here, using single-cell RNA sequencing paired with T receptor sequencing, we profile tissues from ESCC patients accepting and characterize microenvironment context. CXCL13+CD8+ Tex cells, a subset exhausted CD8+ revealed highly infiltrate in pre-treatment tumors show prominent progenitor exhaustion phenotype post-treatment samples responders. We validate cells as predictor improved reveal CXCL13 potentiate anti-PD-1 efficacy vivo. Post-treatment non-responders enriched for notably remarkable TNFRSF4+CD4+ Tregs activated immunosuppressive function significant clone expansion. Several critical markers therapeutic resistance also identified, including LRRC15+ fibroblasts SPP1+ macrophages, which may recruit form an landscape. Overall, our findings unravel immune features distinct treatment, providing rationale optimizing individualized neoadjuvant strategy ESCC. The tumour (ESCC) remain be explored. single TCR on pre- post- identifies presence enrichment marker resistance.

Язык: Английский

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