Journal Article
. 2021 Feb; 40(10):1836-1850.
doi: 10.1038/s41388-020-01636-x.

HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression

Xiaolei Li 1 Xiao Su 1 Rui Liu 1 Yongsha Pan 1 Jiankai Fang 1 Lijuan Cao 1 Chao Feng 1 Qianwen Shang 1 Yongjing Chen 1 Changshun Shao 2 Yufang Shi 3 
  • PMID: 33564072
  •     55 References
  •     18 citations


Despite the widespread use of the blockade of immune checkpoints, for a significant number of cancer patients, these therapies have proven ineffective, presumably due to the immunosuppressive nature of the tumor microenvironment (TME). Critical drivers of immune escape in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immune suppression, but also facilitate metastatic dissemination and impart resistance to immunotherapies. Thus, strategies that convert them into tumor fighters may offer great therapeutic potential. In this study, we evaluated whether pharmacologic modulation of macrophage phenotype by HDAC inhibitors (HDACi) could produce an anti-tumor effect. We demonstrated that low-dose HDACi trichostatin-A (TSA) markedly reshaped the tumor immune microenvironment by modulating the suppressive activity of infiltrating macrophages and inhibiting the recruitment of MDSCs in various tumors. These actions, in turn, augmented anti-tumor immune responses and further enhanced anti-tumor effects of immunotherapies. HDAC inhibition, however, also upregulated PD-L1, thereby limiting the beneficial therapeutic effects. Indeed, combining low-dose TSA with anti-PD-L1 in this model significantly enhanced the durability of tumor reduction and prolonged survival of tumor-bearing mice, compared with the effect of either treatment alone. These data introduce HDAC inhibition as a potential means to harness the anti-tumor potential of macrophages in cancer therapy.

Emerging predictors of the response to the blockade of immune checkpoints in cancer therapy.
Xiaolei Li, Wenhui Song, +2 authors, Weidong Han.
Cell Mol Immunol, 2018 Jul 14; 16(1). PMID: 30002451    Free PMC article.
Lessons learned from the blockade of immune checkpoints in cancer immunotherapy.
Xiaolei Li, Changshun Shao, Yufang Shi, Weidong Han.
J Hematol Oncol, 2018 Feb 28; 11(1). PMID: 29482595    Free PMC article.
Highly Cited. Review.
Harnessing innate immunity in cancer therapy.
Olivier Demaria, Stéphanie Cornen, +3 authors, Eric Vivier.
Nature, 2019 Oct 04; 574(7776). PMID: 31578484
Highly Cited. Review.
Leukocytes in mammary development and cancer.
Lisa M Coussens, Jeffrey W Pollard.
Cold Spring Harb Perspect Biol, 2010 Dec 03; 3(3). PMID: 21123394    Free PMC article.
Trophic macrophages in development and disease.
Jeffrey W Pollard.
Nat Rev Immunol, 2009 Mar 14; 9(4). PMID: 19282852    Free PMC article.
Highly Cited. Review.
The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients.
Catharina Medrek, Fredrik Pontén, Karin Jirström, Karin Leandersson.
BMC Cancer, 2012 Jul 25; 12. PMID: 22824040    Free PMC article.
Highly Cited.
Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer.
Y Ino, R Yamazaki-Itoh, +4 authors, N Hiraoka.
Br J Cancer, 2013 Feb 07; 108(4). PMID: 23385730    Free PMC article.
Highly Cited.
Harnessing tumor-associated macrophages as aids for cancer immunotherapy.
Xiaolei Li, Rui Liu, +4 authors, Yufang Shi.
Mol Cancer, 2019 Dec 07; 18(1). PMID: 31805946    Free PMC article.
Tumour-associated macrophages as treatment targets in oncology.
Alberto Mantovani, Federica Marchesi, +2 authors, Paola Allavena.
Nat Rev Clin Oncol, 2017 Jan 25; 14(7). PMID: 28117416    Free PMC article.
Highly Cited. Review.
Tumor-associated macrophages: from mechanisms to therapy.
Roy Noy, Jeffrey W Pollard.
Immunity, 2014 Jul 19; 41(1). PMID: 25035953    Free PMC article.
Highly Cited. Review.
L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes.
Paulo C Rodriguez, Arnold H Zea, +5 authors, Augusto C Ochoa.
J Immunol, 2003 Jul 23; 171(3). PMID: 12874210
Highly Cited.
Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer.
Nuray Gül, Marjolein van Egmond.
Cancer Res, 2015 Nov 18; 75(23). PMID: 26573795
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Macrophages eliminate circulating tumor cells after monoclonal antibody therapy.
Nuray Gül, Liane Babes, +7 authors, Marjolein van Egmond.
J Clin Invest, 2014 Jan 17; 124(2). PMID: 24430180    Free PMC article.
Highly Cited.
The future of epigenetic therapy in solid tumours--lessons from the past.
Nilofer Azad, Cynthia A Zahnow, Charles M Rudin, Stephen B Baylin.
Nat Rev Clin Oncol, 2013 Apr 03; 10(5). PMID: 23546521    Free PMC article.
Highly Cited. Review.
Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise.
Daphné Morel, Daniel Jeffery, +2 authors, Sophie Postel-Vinay.
Nat Rev Clin Oncol, 2019 Oct 02; 17(2). PMID: 31570827
Highly Cited. Review.
The emerging role of epigenetic therapeutics in immuno-oncology.
Michael J Topper, Michelle Vaz, +2 authors, Stephen B Baylin.
Nat Rev Clin Oncol, 2019 Sep 25; 17(2). PMID: 31548600    Free PMC article.
The Cancer Epigenome: Exploiting Its Vulnerabilities for Immunotherapy.
Helen Loo Yau, Ilias Ettayebi, Daniel D De Carvalho.
Trends Cell Biol, 2018 Aug 30; 29(1). PMID: 30153961
Epigenetic control of CD8+ T cell differentiation.
Amanda N Henning, Rahul Roychoudhuri, Nicholas P Restifo.
Nat Rev Immunol, 2018 Jan 31; 18(5). PMID: 29379213    Free PMC article.
Highly Cited. Review.
Chromatin states define tumour-specific T cell dysfunction and reprogramming.
Mary Philip, Lauren Fairchild, +11 authors, Andrea Schietinger.
Nature, 2017 May 18; 545(7655). PMID: 28514453    Free PMC article.
Highly Cited.
De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.
Hazem E Ghoneim, Yiping Fan, +8 authors, Ben Youngblood.
Cell, 2017 Jun 27; 170(1). PMID: 28648661    Free PMC article.
Highly Cited.
The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis.
Ido Amit, Deborah R Winter, Steffen Jung.
Nat Immunol, 2015 Dec 19; 17(1). PMID: 26681458
Highly Cited. Review.
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
Sadia Saeed, Jessica Quintin, +27 authors, Hendrik G Stunnenberg.
Science, 2014 Sep 27; 345(6204). PMID: 25258085    Free PMC article.
Highly Cited.
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.
Saverio Minucci, Pier Giuseppe Pelicci.
Nat Rev Cancer, 2006 Jan 07; 6(1). PMID: 16397526
Highly Cited. Review.
Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity.
K Cao, G Wang, +12 authors, Y Shi.
Oncogene, 2015 Mar 10; 34(49). PMID: 25745993    Free PMC article.
Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma.
Ashley Orillion, Ayumi Hashimoto, +9 authors, Roberto Pili.
Clin Cancer Res, 2017 Jul 13; 23(17). PMID: 28698201    Free PMC article.
Highly Cited.
Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression.
Zhiqi Xie, Tamami Ikegami, +2 authors, Masashi Tachibana.
Oncoimmunology, 2020 Mar 12; 9(1). PMID: 32158627    Free PMC article.
The cellular and molecular origin of tumor-associated macrophages.
Ruth A Franklin, Will Liao, +5 authors, Ming O Li.
Science, 2014 May 09; 344(6186). PMID: 24812208    Free PMC article.
Highly Cited.
In vitro and in vivo elimination of macrophage tumor cells using liposome-encapsulated dichloromethylene diphosphonate.
N van Rooijen, N Kors, H ter Hart, E Claassen.
Virchows Arch B Cell Pathol Incl Mol Pathol, 1988 Jan 01; 54(4). PMID: 2895535
PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression.
Haidong Tang, Yong Liang, +18 authors, Yang-Xin Fu.
J Clin Invest, 2018 Jan 18; 128(2). PMID: 29337303    Free PMC article.
Highly Cited.
Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression.
Heng Lin, Shuang Wei, +16 authors, Weiping Zou.
J Clin Invest, 2018 Jan 18; 128(2). PMID: 29337305    Free PMC article.
Highly Cited.
Anti-PD-L1 Treatment Results in Functional Remodeling of the Macrophage Compartment.
Huizhong Xiong, Stephanie Mittman, +5 authors, Rafael Cubas.
Cancer Res, 2019 Jan 27; 79(7). PMID: 30679180
Highly Cited.
Macrophage activation and polarization: nomenclature and experimental guidelines.
Peter J Murray, Judith E Allen, +22 authors, Thomas A Wynn.
Immunity, 2014 Jul 19; 41(1). PMID: 25035950    Free PMC article.
Highly Cited.
Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy.
Felix Klug, Hridayesh Prakash, +15 authors, Philipp Beckhove.
Cancer Cell, 2013 Nov 12; 24(5). PMID: 24209604
Highly Cited.
HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen-Loss Variants.
Andrew Nguyen, Louisa Ho, +6 authors, Yonghong Wan.
Cell Rep, 2018 Jul 19; 24(3). PMID: 30021162
Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages.
Stefano Ugel, Francesco De Sanctis, Susanna Mandruzzato, Vincenzo Bronte.
J Clin Invest, 2015 Sep 02; 125(9). PMID: 26325033    Free PMC article.
Highly Cited. Review.
Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease.
Steven J Van Dyken, Richard M Locksley.
Annu Rev Immunol, 2013 Jan 10; 31. PMID: 23298208    Free PMC article.
Highly Cited. Review.
A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships.
Ferdinando Pucci, Mary Anna Venneri, +6 authors, Michele De Palma.
Blood, 2009 Apr 23; 114(4). PMID: 19383967
Highly Cited.
Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.
Jennifer L Guerriero, Alaba Sotayo, +11 authors, Anthony Letai.
Nature, 2017 Mar 09; 543(7645). PMID: 28273064    Free PMC article.
Highly Cited.
Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected.
Douglas Marvel, Dmitry I Gabrilovich.
J Clin Invest, 2015 Jul 15; 125(9). PMID: 26168215    Free PMC article.
Highly Cited. Review.
CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas.
Joseph A Flores-Toro, Defang Luo, +9 authors, Jeffrey K Harrison.
Proc Natl Acad Sci U S A, 2019 Dec 28; 117(2). PMID: 31879345    Free PMC article.
Epigenetic therapy inhibits metastases by disrupting premetastatic niches.
Zhihao Lu, Jianling Zou, +45 authors, Malcolm V Brock.
Nature, 2020 Feb 28; 579(7798). PMID: 32103175    Free PMC article.
The non-canonical NF-κB pathway in immunity and inflammation.
Shao-Cong Sun.
Nat Rev Immunol, 2017 Jun 06; 17(9). PMID: 28580957    Free PMC article.
Highly Cited. Review.
HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment.
Young-Dae Kim, Sang-Min Park, +5 authors, Joong Myung Cho.
J Cancer, 2020 May 06; 11(14). PMID: 32368288    Free PMC article.
Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS.
Maria A Halili, Melanie R Andrews, +11 authors, Matthew J Sweet.
J Leukoc Biol, 2010 Mar 05; 87(6). PMID: 20200406
Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis.
Shu-Nan Cui, Zhao-Yuan Chen, +10 authors, You Shang.
Int Immunopharmacol, 2019 Nov 05; 77. PMID: 31677992
CSF-1R inhibition alters macrophage polarization and blocks glioma progression.
Stephanie M Pyonteck, Leila Akkari, +17 authors, Johanna A Joyce.
Nat Med, 2013 Sep 24; 19(10). PMID: 24056773    Free PMC article.
Highly Cited.
Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study.
Nicholas Butowski, Howard Colman, +15 authors, Michael Prados.
Neuro Oncol, 2015 Oct 10; 18(4). PMID: 26449250    Free PMC article.
Highly Cited.
Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma.
Timothy M Nywening, Brian A Belt, +12 authors, David C Linehan.
Gut, 2017 Dec 03; 67(6). PMID: 29196437    Free PMC article.
Highly Cited.
The CCL3 family of chemokines and innate immunity cooperate in vivo in the eradication of an established lymphoma xenograft by rituximab.
Elena Cittera, Marzia Leidi, +6 authors, Josée Golay.
J Immunol, 2007 May 04; 178(10). PMID: 17475893
Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies.
Ailsa J Christiansen, Alison West, +4 authors, Ricky W Johnstone.
Proc Natl Acad Sci U S A, 2011 Mar 04; 108(10). PMID: 21368108    Free PMC article.
Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate.
Sorin Armeanu, Michael Bitzer, +9 authors, Helmut R Salih.
Cancer Res, 2005 Jul 19; 65(14). PMID: 16024634
Highly Cited.
Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B.
Søren Skov, Marianne Terndrup Pedersen, +3 authors, Niels Odum.
Cancer Res, 2005 Dec 03; 65(23). PMID: 16322264
Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis.
Johannes Laengle, Julijan Kabiljo, +4 authors, Michael Bergmann.
J Immunother Cancer, 2020 Jan 16; 8(1). PMID: 31940587    Free PMC article.
Low-dose HDACi potentiates anti-tumor activity of macrophages in immunotherapy.
Xiaolei Li, Hanren Dai, Hua Wang.
Oncoimmunology, 2021 Jun 15; 10(1). PMID: 34123577    Free PMC article.
Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1.
Hao Cai, Yichi Zhang, Jian Wang, Jinyang Gu.
Front Immunol, 2021 Jul 13; 12. PMID: 34248982    Free PMC article.
HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity.
Dimitris Karagiannis, Theodoros Rampias.
Cancers (Basel), 2021 Jul 25; 13(14). PMID: 34298787    Free PMC article.
Characterization of Histone Deacetylase Mechanisms in Cancer Development.
Rihan Hai, Liuer He, Guang Shu, Gang Yin.
Front Oncol, 2021 Aug 17; 11. PMID: 34395273    Free PMC article.
Histone Modifying Enzymes as Targets for Therapeutic Intervention in Oesophageal Adenocarcinoma.
Oliver J Pickering, Stella P Breininger, Timothy J Underwood, Zoë S Walters.
Cancers (Basel), 2021 Aug 28; 13(16). PMID: 34439236    Free PMC article.
Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy.
Marine M Leblond, Hana Zdimerova, Emma Desponds, Grégory Verdeil.
Cancers (Basel), 2021 Sep 29; 13(18). PMID: 34572939    Free PMC article.
Functionalized Nanoparticles Targeting Tumor-Associated Macrophages as Cancer Therapy.
Yuanyuan He, Raimundo Fernandes de Araújo Júnior, Luis J Cruz, Christina Eich.
Pharmaceutics, 2021 Oct 24; 13(10). PMID: 34683963    Free PMC article.
Acetylation in Tumor Immune Evasion Regulation.
Jun Lu, Xiang He, +2 authors, Wenzheng Li.
Front Pharmacol, 2021 Dec 10; 12. PMID: 34880761    Free PMC article.
Overview of the microbiota in the gut-liver axis in viral B and C hepatitis.
Maria Adriana Neag, Andrei Otto Mitre, Adrian Catinean, Anca Dana Buzoianu.
World J Gastroenterol, 2021 Dec 11; 27(43). PMID: 34887642    Free PMC article.
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy.
Enyong Dai, Zhi Zhu, +3 authors, Zong Sheng Guo.
Mol Cancer, 2021 Dec 22; 20(1). PMID: 34930302    Free PMC article.
Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers.
Maria Gracia-Hernandez, Zuleima Munoz, Alejandro Villagra.
Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944799    Free PMC article.
Therapeutic Targets in Diffuse Midline Gliomas-An Emerging Landscape.
Elisha Hayden, Holly Holliday, +4 authors, David S Ziegler.
Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944870    Free PMC article.
Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy.
Maria Fortunata Lofiego, Sara Cannito, +11 authors, On Behalf Of The EPigenetic Immune-Oncology Consortium Airc Epica Investigators.
Epigenomes, 2021 Dec 31; 5(4). PMID: 34968251    Free PMC article.
Combination of Radiosensitivity Gene Signature and PD-L1 Status Predicts Clinical Outcome of Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: A Study Based on The Cancer Genome Atlas Dataset.
Dongjun Dai, Yinglu Guo, +3 authors, Qichun Wei.
Front Mol Biosci, 2022 Jan 01; 8. PMID: 34970597    Free PMC article.
Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention.
Dusan Ruzic, Nemanja Djoković, +3 authors, Juan F Santibanez.
Pharmaceutics, 2022 Jan 22; 14(1). PMID: 35057104    Free PMC article.
HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma.
Wenjie Gong, Lei Wang, +11 authors, Leopold Sellner.
Biomedicines, 2022 Feb 26; 10(2). PMID: 35203582    Free PMC article.
Transcriptional and post-transcriptional regulation of checkpoint genes on the tumour side of the immunological synapse.
Paula Dobosz, Przemysław A Stempor, Miguel Ramírez Moreno, Natalia A Bulgakova.
Heredity (Edinb), 2022 Apr 24;. PMID: 35459932
Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets.
Yan Tie, Fan Tang, Yu-Quan Wei, Xia-Wei Wei.
J Hematol Oncol, 2022 May 19; 15(1). PMID: 35585567    Free PMC article.