Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype

Nature Communications
Degao ChenBo Huang

Abstract

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.

References

Sep 1, 1994·Parasite : Journal De La Société Française De Parasitologie·G CambieH Ginsburg
Feb 3, 1999·Molecular Pharmacology·J ChenR L Rosenberg
Feb 15, 2001·The New England Journal of Medicine·A DjimdéC V Plowe
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Stanford L PengLaurie H Glimcher
Oct 26, 2006·Nature Reviews. Immunology·Gavin P DunnRobert D Schreiber
Jun 27, 2009·Science·Marco SardielloAndrea Ballabio
Dec 10, 2009·Nature Reviews. Molecular Cell Biology·Joseph R CaseyJohn Orlowski
Sep 22, 2010·Nature Immunology·Subhra K Biswas, Alberto Mantovani
Oct 16, 2010·The Journal of Biological Chemistry·Chad D TouchberryMichael J Wacker
Nov 12, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Biao ZhangBo Huang
Jun 8, 2011·Antimicrobial Agents and Chemotherapy·Brioni R MooreKevin T Batty
Jul 15, 2011·Human Molecular Genetics·Michela PalmieriAndrea Ballabio
Oct 14, 2011·The Biochemical Journal·Anthony J MorganAntony Galione
Jun 14, 2012·Science Signaling·Agnes Roczniak-FergusonShawn M Ferguson
Jan 5, 2013·Cancer Research·Tomonori KimuraYoshitaka Isaka
Mar 23, 2013·Cancer Cell·Michele De Palma, Claire E Lewis
Apr 23, 2013·Immunity·Erika L Pearce, Edward J Pearce
Apr 24, 2013·Nature Reviews. Molecular Cell Biology·Carmine SettembreAndrea Ballabio
Apr 26, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Julia ParnisChristiane Nolte
May 30, 2013·Trends in Molecular Medicine·Hannelore MaesPatrizia Agostinis
Aug 7, 2013·Journal of Molecular Cell Biology·Hanna AppelqvistKarin Öllinger
Aug 21, 2013·Nature Reviews. Immunology·J Simon C Arthur, Steven C Ley
Jan 15, 2014·Current Opinion in Immunology·Hiroyoshi Nishikawa, Shimon Sakaguchi
Jul 6, 2014·Liver International : Official Journal of the International Association for the Study of the Liver·Fatma E MohamedRajiv Jalan
Jul 19, 2014·Immunity·Slava EpelmanGwendalyn J Randolph
Jul 19, 2014·Immunity·Roy Noy, Jeffrey W Pollard
Aug 5, 2014·Nature Immunology·Stanley Ching-Cheng HuangEdward J Pearce
Aug 15, 2014·Cancer Cell·Hannelore MaesPeter Carmeliet
Aug 29, 2014·Molecular Biology of the Cell·Johnathan CantonSergio Grinstein
Dec 6, 2014·Cancer Immunology Research·Huafeng ZhangBo Huang
Feb 28, 2015·Nature Cell Biology·Diego L MedinaAndrea Ballabio
Mar 11, 2015·The Journal of Experimental Medicine·Alberto Mantovani, Paola Allavena
Mar 17, 2015·Trends in Immunology·Renato OstuniGioacchino Natoli

❮ Previous
Next ❯

Citations

Oct 16, 2018·Journal of Cellular Biochemistry·Masoud NajafiKeywan Mortezaee
Dec 7, 2018·Journal of Cellular Physiology·Bagher FarhoodKeywan Mortezaee
Nov 1, 2018·Journal of Cellular Physiology·Masoud NajafiKeywan Mortezaee
Nov 19, 2019·Cell Cycle·Christina G Towers, Andrew Thorburn
Sep 21, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shengzhou ShanQingfeng Li
Jun 4, 2020·Journal for Immunotherapy of Cancer·Yong LiDaping Fan
Jul 4, 2019·International Journal of Oncology·Wei WangZixue Xuan Xuan
Jul 28, 2020·EMBO Molecular Medicine·Eliise Laura NirkMario Mauthe
May 19, 2020·American Journal of Respiratory and Critical Care Medicine·Lisa ScheuermannAnca Dorhoi
Aug 12, 2020·JCI Insight·Gaurav SharmaRavi K Amaravadi
Sep 27, 2019·Nature Communications·Tao YuYichuan Xiao
Oct 3, 2018·Journal of Cellular Biochemistry·Masoud NajafiKeywan Mortezaee
Nov 23, 2019·The Journal of Cell Biology·Christina G TowersAndrew Thorburn
Mar 3, 2020·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Jingxing Yang, Chunfu Zhang
Oct 24, 2018·Frontiers in Immunology·Emile J ClappaertDamya Laoui
Aug 24, 2019·Journal of Hematology & Oncology·Xinyu TianShengjun Wang
Sep 27, 2019·Inhalation Toxicology·Rachel BurmeisterAndrij Holian
Apr 22, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yang ZhouHuile Gao
Dec 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Floris J van DalenOlga Ilina
Jul 1, 2020·Cells·Anastasiya S PoltavetsTimur Kh Fatkhudinov
May 13, 2020·Cancers·Trace M JonesSteffan T Nawrocki
Aug 23, 2019·Cancer Discovery·Ravi K AmaravadiJayanta Debnath
Dec 1, 2020·Molecular Oncology·Elena AstaninaGabriella Doronzo
Jul 17, 2019·European Journal of Pharmacology·Marina StamenkovicVladimir Trajkovic
Nov 12, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Huan ShenJunbo Gong
Nov 11, 2019·Neurobiology of Disease·Zahra AfghahJonathan D Geiger
Jan 16, 2021·Chemical Reviews·Mukaddes IzciStefaan J Soenen
Dec 22, 2020·Frontiers in Cellular and Infection Microbiology·Lidia Szulc-DąbrowskaFelix N Toka

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
ELISA
nuclear translocation
PCR
Assay
electrophoresis

Software Mentioned

OLYMPUS
Graphpad
FlowJo

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Cellular Immunometabolism

Immunometabolism involves not only the way metabolites are digested by the immune system, but the way in which they can alter the pathway of the immune system. These responses occur in day-to-day healthy cell functioning, but can result in diseases, such as autoimmune disorders. Discover the latest research on cellular immunometabolism here.

BioHub - Researcher Network

The Chan-Zuckerberg Biohub aims to support the fundamental research and develop the technologies that will enable physicians to cure, prevent, or manage all diseases in our childrens' lifetimes. The CZ Biohub brings together researchers from UC Berkeley, Stanford, and UCSF. Find the latest research from the CZ Biohub researcher network here.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.