A microphysiological system reveals neutrophil contact-dependent attenuation of pancreatic tumor progression by CXCR2 inhibition-based immunotherapy DOI Creative Commons
Shuai Shao, Nikkí A. Delk, Caroline N. Jones

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 4, 2023

Abstract Cancer cells recruit neutrophils from the bloodstream into tumor tissue, where these immune promote progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, mechanisms which humans, as well how potentially serve cancer therapy, remain elusive. In this study, we developed human cell-based microphysiological system quantify neutrophil-tumor spheroid interactions both “separated” and “contact” scenarios. We found invasion spheroids through secretion soluble factors direct contact with cells. However, they proliferation solely contact. Interestingly, treatment AZD-5069, inhibitor, attenuates neutrophils. Our findings show reduces migration toward spheroids. These results shed new light on tumor-promoting tumor-suppressive may aid design optimization novel immunotherapeutic strategies based

Language: Английский

Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001 DOI Creative Commons
Christopher Montemagno, Arnaud Jacquel,

Charlotte Pandiani

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: March 19, 2024

Abstract Background In clear cell renal carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC by concurrently using CXCR2 inhibitors alongside immunotherapies. Methods We analyzed ELR + CXCL levels their correlation patient survival during immunotherapy. RCT001, unique inhibitor, was examined for its mechanism action, particularly effects on human primary macrophages. tested synergistic impact RCT001 in combination immunotherapies both mouse models presence PBMC. Resuts Elevated cytokine were found to correlate reduced overall our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis reducing viability cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against tumor. models, enhanced efficacy anti-CTLA4 anti-PD1 tumor-associated M2 neutrophils. also impacted activation CD4 T lymphocytes, immune-tolerant lymphocytes while increasing activated natural killer dendritic Similar effectiveness observed RCC tumors when combined anti-PD-1 treatment. Conclusions through mechanism, suppresses proliferation, angiogenesis, polarization. This optimization potentiates immunotherapy holds promise significantly improving prospects metastatic patients.

Language: Английский

Citations

12

Association of preoperative aspartate aminotransferase to platelet ratio index with outcomes and tumour microenvironment among colorectal cancer with liver metastases DOI Creative Commons

Qichen Chen,

Yiqiao Deng,

Yuan Li

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 588, P. 216778 - 216778

Published: March 6, 2024

This study aims to investigate applicable robust biomarkers that can improve prognostic predictions for colorectal liver metastasis (CRLM) patients receiving simultaneous resection. A total of 1323 CRLM from multiple centres were included. The preoperative aspartate aminotransferase platelet ratio index (APRI) level blood obtained. Patients stratified into a high APRI group and low group, comparisons conducted by analyzing progression-free survival (PFS), overall (OS) postoperative early recurrence. Tumour samples collected perform single-cell RNA sequencing multiplex immunohistochemistry/immunofluorescence (mIHC/IF) the association levels tumour microenvironment CRLM. Compared with <0.33, PFS disadvantage (IPTW-adjusted HR = 1.240, P 0.015) OS (IPTW- adjusted 1.507, 0.002) ≥0.33 preserved in IPTW-adjusted Cox hazards regression analyses. An ≥0.25 was associated significantly increased risk recurrence after adjustment OR 1.486, 0.001). external validation showed consistent results training cohort. In revealed heightened malignancy epithelial cells, enrichment inflammatory-like cancer-associated fibroblasts SPP1+ macrophages activation malignant cells fibrotic microenvironment, more suppressed-function T cells; mIHC/IF PD1+ CD4+ FOXP3+ CD8+ iCAFs intratumoral region peritumoral region. contributed valuable evidence regarding predicting prognoses among resection provided underlying clues supporting between clinical outcomes bioinformatics analysis mIHC/IF.

Language: Английский

Citations

8

Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches DOI
Ming Gu, Yang Liu, Xin Peng

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 588, P. 216738 - 216738

Published: Feb. 23, 2024

Language: Английский

Citations

7

The role of CXC chemokines and receptors in breast cancer DOI Creative Commons
Mahdi Masrour, Aysan Moeinafshar, Amirhossein Poopak

et al.

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 25, 2025

Language: Английский

Citations

1

Small Molecule Targeting Immune Cells: A Novel Approach for Cancer Treatment DOI Creative Commons
Shilpi Singh, Debashis Barik, Ananta Prasad Arukha

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2621 - 2621

Published: Sept. 24, 2023

Conventional and cancer immunotherapies encompass diverse strategies to address various types stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, high toxicity, leading suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune non-immune cells dictating progression. An innovative avenue therapy involves leveraging small molecules influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled phenotypically cohort innate-like T (ILT) hybrid (HCs) exhibiting novel characteristics, including augmented proliferation, migration, exhaustion, evasion immunosurveillance, reduced apoptosis, drug resistance, heightened metastasis frequency. Leveraging small-molecule immunomodulators target players presents an exciting frontier developing immunotherapies. Moreover, molecule modulators with immunotherapy can synergistically enhance inhibitory impact on progression empowering system meticulously fine-tune responses TME, bolstering its capacity recognize eliminate cells. This review outlines involving that modify potentially revolutionizing therapeutic interventions enhancing anti-tumor response.

Language: Английский

Citations

14

Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis DOI Creative Commons
Leng Han,

Lingjun Meng,

Jiao Liu

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 604, P. 217258 - 217258

Published: Sept. 13, 2024

Language: Английский

Citations

6

Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance DOI Open Access

Shauna McClelland,

Pamela Maxwell,

Cristina Branco

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(16), P. 2797 - 2797

Published: Aug. 8, 2024

This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 CXCR2, in prostate cancer (PCa), particularly castration-resistant (CRPC) metastatic CRPC (mCRPC). emphasizes crucial role tumour microenvironment (TME) inflammatory cytokines promoting progression response to cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) 2 (CXCR2), modulates multiple signalling pathways, enhancing angiogenesis, proliferation, migration cells. highlights shift PCa research focus from solely cells non-cancer-cell components, including vascular endothelial cells, extracellular matrix, immune dynamic interactions within TME. The immunosuppressive nature TME significantly influences resistance emerging therapies. Current treatment modalities, androgen deprivation therapy chemotherapeutics, encounter persistent are complicated by cancer’s notably “immune-cold” nature, which limits system tumour. These challenges underscore critical need for novel approaches that both overcome enhance engagement therapeutic potential inhibiting IL-8 is explored, with studies showing enhanced sensitivity treatments, radiation inhibitors. Clinical trials, such as ACE trial, demonstrate efficacy combining CXCR2 inhibitors existing offering significant benefits, especially patients resistant PCa. also addresses chemokines, noting complexity precision avoid side effects optimize outcomes.

Language: Английский

Citations

5

Living Cell‐Derived Intelligent Nanobots for Precision Oncotherapy DOI
Liqiang Zhou, Kun Li, Yingying Liu

et al.

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 34(10)

Published: Nov. 23, 2023

Abstract The progress of precision oncology medicine is always limited by the tumor off‐targeting, drug side effects, and treatment inefficiency due to complex ever‐changing microenvironment. Living cells, such as blood cells immune exhibit natural tropism, controllable physicochemical modification, excellent biocompatibility, which provide an advantageous pathway for innovative efficient suppression. Armed with nanoengineering techniques, artificial living harness their inherent biological properties precisely identify eradicate tumors, demonstrating broad application prospects great transformational potential in personalized cancer therapy. Here, recent advances cell‐based bionanobots including platelets, red neutrophil, macrophage, CAR‐T therapy regulation are summarized, anti‐tumor strategies engineering cell nanorobots overcome barriers suppression also outlined (e.g., immunotherapy, sonodynamic therapy, chemo/radiotherapy, phototherapy). In addition, study discusses advantages, limitations, current challenges delivery systems, perspectives on future development cell‐mediated nanomedicine.

Language: Английский

Citations

10

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma DOI
Lin Dong,

Chao Liu,

Haoyang Sun

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 593, P. 216956 - 216956

Published: May 11, 2024

Language: Английский

Citations

4

Modulating the CXCR2 Signaling Axis Using Engineered Chemokine Fusion Proteins to Disrupt Myeloid Cell Infiltration in Pancreatic Cancer DOI Creative Commons

Benjamin Christopher,

Lena Golick,

Ashton Basar

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(5), P. 645 - 645

Published: April 30, 2025

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates all cancers, and limited treatment options exist. Immunotherapy is effective in some cancer types, but immunosuppressive tumor microenvironment (TME) PDAC a barrier to immunotherapy. CXCR2+ myeloid-derived suppressor cells (MDSCs) are abundant tumors humans mouse models. MDSCs suppress effector cell function, making them attractive targets for restoring anti-tumor immunity. In this study, we show that most soluble factors released from genetically diverse set human CXCR2 ligands, including CXCL8, CXCL5, CXCL1. Expression ligands at least partially dependent on mutant KRAS NFκB signaling, which two commonly dysregulated pathways PDAC. We prevalent immune tumors. expressed high levels CXCR2, found myeloid readily migrate toward conditioned media (CM) prepared cultures. designed ligand-Fc fusion proteins modulate chemotactic signaling axis. Unexpectedly, these were superior native chemokines binding activation cells. These “superkines” potent inhibitors CM-induced migration small-molecule neutralizing antibodies. Our findings suggest superkines may disrupt recruitment tumors, ultimately improving immunotherapy outcomes patients with

Language: Английский

Citations

0