A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer

Bao, Xuanwen; Li, Qiong; Chen, Dong; Dai, Xiaomeng; Liu, Chuan; Tian, Weihong; Zhang, Hangyu; Jin, Yuzhi; Wang, Yin; Cheng, Jinlin; Lai, Chunyu; Ye, Chanqi; Xin, Shan; Li, Xin; Su, Ge; Ding, Yongfeng; Xiong, Yangyang; Xie, Jindong; Tano, Vincent; Wang, Yanfang; Fu, Wenguang; Deng, Shuiguang; Fang, Weijia; Sheng, Jianpeng; Ruan, Jian; Zhao, Peng

doi:10.1016/j.xcrm.2024.101399

Cited by 6 publications

(1 citation statement)

References 76 publications

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“…Indeed, a number of recent studies suggest this may be the case. For example, Bao et al 35 revealed a close cell-to-cell interaction between a subset of FR-β+MRC1+ TAMs and inactive (mainly PD-1-) CD8+T cells in human colorectal carcinomas. Furthermore, depletion of FR-β+ TAMs expressing a transcriptional profile typical of PV TAMs (ie, mrc1 , Lyve1, Hmox1,Il10 and stab1 ) in a mouse model of ovarian cancer increased the frequency and activation of ascitic CD8+T cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Al-janabi,

Moyes,

Allen

et al. 2024

J Immunother Cancer

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BackgroundAndrogen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC.MethodsWe used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2′3′-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT.ResultsTAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs.ConclusionTogether, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Al-janabi,

Moyes,

Allen

et al. 2024

J Immunother Cancer

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Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma

Wu,

Zhang,

Wang

et al. 2024

Oncogene

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Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy

Li,

Geng,

Luo

et al. 2024

Sig Transduct Target Ther

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Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

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A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer

Cited by 6 publications

References 76 publications

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma

Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy

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