Volume 13 Issue 7
Jul.  2023
Turn off MathJax
Article Contents
Xiaofan Sun, Lisha Zhou, Yi Wang, Guoliang Deng, Xinran Cao, Bowen Ke, Xiaoqi Wu, Yanhong Gu, Haibo Cheng, Qiang Xu, Qianming Du, Hongqi Chen, Yang Sun. Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 726-744. doi: 10.1016/j.jpha.2023.04.013
Citation: Xiaofan Sun, Lisha Zhou, Yi Wang, Guoliang Deng, Xinran Cao, Bowen Ke, Xiaoqi Wu, Yanhong Gu, Haibo Cheng, Qiang Xu, Qianming Du, Hongqi Chen, Yang Sun. Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 726-744. doi: 10.1016/j.jpha.2023.04.013

Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

doi: 10.1016/j.jpha.2023.04.013

This work was supported by the National Key Research and Development Plan, China (Grant No.: 2022YFC3500202), the Natural Science Foundation of China (Grant Nos.: 82172558, and 82205024), the Scientific and Technological Innovation Action Plan of Natural Science Foundation Project of Shanghai, China (Grant No.: 22ZR1447400), the Scientific and Technological Innovation Action Plan, China (Grant No.: 22ZR1447400), the Fundamental Research Funds for the Central Universities, China (Grant Nos.: 020814380179, and 020814380174), the Distinguished Young Scholars of Nanjing, China (Grant No.: JQX20008), and the School of Life Science (NJU)-Sipimo Joint Funds and Mountain Climbing Talents Project of Nanjing University, China (Grant No.: 2015018).

  • Received Date: Dec. 19, 2022
  • Accepted Date: Apr. 18, 2023
  • Rev Recd Date: Apr. 12, 2023
  • Publish Date: Apr. 22, 2023
  • Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
  • loading
  • F. Ciardiello, D. Ciardiello, G. Martini, et al., Clinical management of metastatic colorectal cancer in the era of precision medicine. CA A Cancer J. Clin., 72 (2022) 372-401.
    R.L. Siegel, K.D. Miller, A. Goding Sauer, et al., Colorectal cancer statistics, 2020. CA A Cancer J. Clin., 70 (2020) 145-164.
    K. Ganesh, Z.K. Stadler, A. Cercek, et al., Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol., 16 (2019) 361-375.
    K. Ganesh, Optimizing immunotherapy for colorectal cancer. Nat. Rev. Gastroenterol. Hepatol., 19 (2022) 93-94.
    S.P. Kubli, T. Berger, D.V. Araujo, et al., Beyond immune checkpoint blockade: emerging immunological strategies. Nat. Rev. Drug Discov., 20 (2021) 899-919.
    M. Schmitt and F.R. Greten, The inflammatory pathogenesis of colorectal cancer. Nat. Rev. Immunol., 21 (2021) 653-667.
    Y. Tie, F. Tang, Y.Q. Wei, et al., Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J. Hematol. Oncol., 15 (2022) 61.
    D.G. DeNardo and B. Ruffell, Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol., 19 (2019) 369-382.
    A. Mantovani, P. Allavena, F. Marchesi, et al., Macrophages as tools and targets in cancer therapy. Nat. Rev. Drug Discov., 21 (2022) 799-820.
    X. Xiang, J. Wang, D. Lu, et al., Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct. Targeted Ther., 6 (2021) 75.
    P.J. Murray, J.E. Allen, S.K. Biswas, et al., Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity, 41 (2014) 14-20.
    R. Stienstra, R.T. Netea-Maier, N.P. Riksen, et al., Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Cell Metabol., 26 (2017) 142-156.
    J. Van den Bossche, L.A. O'Neill, and D. Menon, Macrophage immunometabolism: where are we (going)? Trends Immunol., 38 (2017) 395-406.
    M. Zhang, X. Pan, K. Fujiwara, et al., Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism. Signal Transduct. Targeted Ther., 6 (2021) 366.
    J.L. Wilson and T. Weichhart, TORching a semaphore for alternative macrophage activation. Nat. Immunol., 19 (2018) 512-514.
    S. Kang, Y. Nakanishi, Y. Kioi, et al., Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization. Nat. Immunol., 19 (2018) 561-570.
    R. Dash, M.C. Ali, I. Jahan, et al., Emerging potential of cannabidiol in reversing proteinopathies. Ageing Res. Rev., 65 (2021) 101209.
    P. Grimison, A. Mersiades, A. Kirby, et al., Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial. Ann. Oncol., 31 (2020) 1553-1560.
    A. Oláh, B.I. Tóth, I. Borbíró, et al., Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J. Clin. Invest., 124 (2014) 3713-3724.
    M. Rajesh, P. Mukhopadhyay, S. Batkai, et al., Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J. Am. Coll. Cardiol., 56 (2010) 2115-2125.
    T. Huang, T. Xu, Y. Wang, et al., Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy, 17 (2021) 3592-3606.
    A. Shrivastava, P.M. Kuzontkoski, J.E. Groopman, et al., Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol. Cancer Therapeut., 10 (2011) 1161-1172.
    B. Kis, F.C. Ifrim, V. Buda, et al., Cannabidiol-from plant to human body: a promising bioactive molecule with multi-target effects in cancer. Int. J. Mol. Sci., 20 (2019) 5905.
    L. Lyon, THC and CBD: is medical cannabis overhyped or under-prescribed? Brain, 143 (2020) e34.
    S.C. Britch, S. Babalonis, and S.L. Walsh, Cannabidiol: pharmacology and therapeutic targets. Psychopharmacology, 238 (2021) 9-28.
    E. Driehuis, K. Kretzschmar, and H. Clevers, Establishment of patient-derived cancer organoids for drug-screening applications. Nat. Protoc., 15 (2020) 3380-3409.
    A. Butler, P. Hoffman, P. Smibert, et al., Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol., 36 (2018) 411-420.
    G. Yu, L.G. Wang, Y. Han, et al., clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS., 16 (2012) 284-287.
    T. Stuart, A. Butler, P. Hoffman, et al., Comprehensive integration of single-cell data. Cell, 177 (2019) 1888-1902 e21.
    J.M. Granja, M.R. Corces, S.E. Pierce, et al., ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet., 53 (2021) 403-411.
    I. Korsunsky, N. Millard, J. Fan, et al., Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods, 16 (2019) 1289-1296.
    D. van Dijk, R. Sharma, J. Nainys, et al., Recovering gene interactions from single-cell data using data diffusion. Cell, 174 (2018) 716-729 e27.
    Y. Zhang, T. Liu, C.A. Meyer, et al., Model-based analysis of ChIP-seq (MACS). Genome Biol., 9 (2008) R137.
    C. Trapnell, D. Cacchiarelli, J. Grimsby, et al., The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol., 32 (2014) 381-386.
    X. Qiu, A. Hill, J. Packer, et al., Single-cell mRNA quantification and differential analysis with Census. Nat. Methods, 14 (2017) 309-315.
    X. Qiu, Q. Mao, Y. Tang, et al., Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods, 14 (2017) 979-982.
    A. Subramanian, P. Tamayo, V.K. Mootha, et al., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA, 102 (2005) 15545-15550.
    S. Hänzelmann, R. Castelo, and J. Guinney, GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf., 14 (2013) 7.
    S. Jin, C.F. Guerrero-Juarez, L. Zhang, et al., Inference and analysis of cell-cell communication using CellChat. Nat. Commun., 12 (2021) 1088.
    Y.J. Li, C. Zhang, A. Martincuks, et al., STAT proteins in cancer: orchestration of metabolism. Nat. Rev. Cancer, 23 (2023) 115-134.
    A. Kauppinen, T. Suuronen, J. Ojala, et al., Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell. Signal., 25 (2013) 1939-1948.
    J. Qi, H. Sun, Y. Zhang, et al., Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nat. Commun., 13 (2022) 1742.
    M. Faas, N. Ipseiz, J. Ackermann, et al., IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation. Immunity, 54 (2021) 2531-2546 e5.
    S.Y. Weng, X. Wang, S. Vijayan, et al., IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal. EBioMedicine, 29 (2018) 92-103.
    K. Mehla and P.K. Singh, Metabolic regulation of macrophage polarization in cancer. Trends Cancer, 5 (2019) 822-834.
    M.M. Kaneda, K.S. Messer, N. Ralainirina, et al., PI3Kgamma is a molecular switch that controls immune suppression. Nature, 539 (2016) 437-442.
    E. Vergadi, E. Ieronymaki, K. Lyroni, et al., Akt signaling pathway in macrophage activation and M1/M2 polarization. J. Immunol., 198 (2017) 1006-1014.
    A.J. Covarrubias, H.I. Aksoylar, J. Yu, et al., Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife, 5 (2016) 11612.
    X. Li, R. Liu, X. Su, et al., Harnessing tumor-associated macrophages as aids for cancer immunotherapy. Mol. Cancer, 18 (2019) 177.
    H.M. Chen, W. van der Touw, Y.S. Wang, et al., Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J. Clin. Invest., 128 (2018) 5647-5662.
    A.N. Chamseddine, T. Assi, O. Mir, et al., Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: a TAM-pting approach. Pharmacol. Ther., 231 (2022) 107986.
    C.W. Wanderley, D.F. Colón, J.P.M. Luiz, et al., Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res., 78 (2018) 5891-5900.
    L. Sun, T. Kees, A.S. Almeida, et al., Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell, 39 (2021) 1361-1374 e9.
    C. Gross, D.A. Ramirez, S. McGrath, et al., Cannabidiol induces apoptosis and perturbs mitochondrial function in human and canine glioma cells. Front. Pharmacol., 12 (2021) 725136.
    P. Massi, A. Vaccani, S. Ceruti, et al., Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J. Pharmacol. Exp. Therapeut., 308 (2004) 838-845.
    S. Jeong, H.K. Yun, Y.A. Jeong, et al., Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells. Cancer Lett., 447 (2019) 12-23.
    S. Jeong, B.G. Kim, D.Y. Kim, et al., Cannabidiol overcomes Oxaliplatin resistance by enhancing NOS3- and SOD2-induced autophagy in human colorectal cancer cells. Cancers, 11 (2019) 781.
    Y. Zhu, Z. Ouyang, H. Du, et al., New opportunities and challenges of natural products research: when target identification meets single-cell multiomics. Acta Pharm. Sin. B, 12 (2022) 4011-4039.
    G. Deng, L. Zhou, B. Wang, et al., Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation. J. Immunother. Cancer, 10 (2022) e004874.
    E. Sanchez-Lopez, Z. Zhong, A. Stubelius, et al., Choline uptake and metabolism modulate macrophage IL-1beta and IL-18 production. Cell Metabol., 29 (2019) 1350-1362 e7.
    X. Xiong, S. Chen, J. Shen, et al., Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2. Signal Transduct. Targeted Ther., 7 (2022) 99.
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (377) PDF downloads(80) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint