Abstract
Background Heat shock proteins (HSPs) are molecular chaperones, which support tumorigenesis by sustaining various hallmarks of cancer. It is now well established that HSPs play critical roles not only inside but also outside the cell. In the extracellular milieu, HSPs exert their actions by regulating various effector cells of the immune system. This chapter will explore the latest findings on the role of HSPs in tumor immunity.
Methods The chapter will review (i) the immunologic aspects of HSP functions in cancer and (ii) roles of extracellular HSPs in tumor immunity.
Results Recently, the involvement of HSPs in the regulation of tumor immunity has been revealed. In particular, the distinct functions of intracellular and extracellular HSPs in the regulation of innate and adaptive immune responses.
Conclusions HSPs are molecular chaperones, which may act on various components of the immune system, including macrophages, dendritic cells, and B, T, and NK cells. Further studying the mechanisms by which HSPs affect immune cells may provide the basis for the discovery of new therapeutic targets for the treatment of cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aghamollaei H, Ghanei M, Rasaee MJ, Latifi AM, Bakherad H, Fasihi-Ramandi M, Taheri RA, Gargari SLM (2021) Isolation and characterization of a novel nanobody for detection of GRP78 expressing cancer cells. Biotechnol Appl Biochem 68(2):239–246. https://doi.org/10.1002/bab.1916
Albakova Z, Mangasarova Y (2021) The HSP immune network in cancer. Front Immunol 12(5162). https://doi.org/10.3389/fimmu.2021.796493
Albakova Z, Armeev GA, Kanevskiy LM, Kovalenko EI, Sapozhnikov AM (2020) HSP70 multi-functionality in cancer. Cells 9(3). https://doi.org/10.3390/cells9030587
Albakova Z, Siam MKS, Sacitharan PK, Ziganshin RH, Ryazantsev DY, Sapozhnikov AM (2021a) Extracellular heat shock proteins and cancer: new perspectives. Trans Oncol 14(2):100995. https://doi.org/10.1016/j.tranon.2020.100995
Albakova Z, Norinho DD, Mangasarova Y, Sapozhnikov A (2021b) Heat shock proteins in urine as cancer biomarkers. Front Med (Lausanne) 8(1748). https://doi.org/10.3389/fmed.2021.743476
Albakova Z, Mangasarova Y, Sapozhnikov A (2021c) Heat shock proteins in lymphoma immunotherapy. Front Immunol 12(769). https://doi.org/10.3389/fimmu.2021.660085
Albakova Z, Mangasarova Y, Albakov A, Nikulina E, Kravchenko S, Sapozhnikov A (2022) Aberrant HSP90 expression in lymphocytes and HSP90 response to anti-PD-1 therapy in lymphoma patients. Front Immunol 13. https://doi.org/10.3389/fimmu.2022.893137
Albakova Z, Mangasarova Y, Albakov A, Gorenkova L. HSP70 and HSP90 in cancer: cytosolic, endoplasmic reticulum and mitochondrial chaperones of tumorigenesis. Front Oncol:17
Al-Hashimi AA, Caldwell J, Gonzalez-Gronow M, Pizzo SV, Aboumrad D, Pozza L, Al-Bayati H, Weitz JI, Stafford A, Chan H, Kapoor A, Jacobsen DW, Dickhout JG, Austin RC (2010) Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores. J Biol Chem 285(37):28912–28923. https://doi.org/10.1074/jbc.M110.119107
Arbore G, West EE, Spolski R, Robertson AAB, Klos A, Rheinheimer C, Dutow P, Woodruff TM, Yu ZX, O’Neill LA, Coll RC, Sher A, Leonard WJ, Köhl J, Monk P, Cooper MA, Arno M, Afzali B, Lachmann HJ, Cope AP, Mayer-Barber KD, Kemper C (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science (New York, NY) 352(6292):aad1210. https://doi.org/10.1126/science.aad1210
Arispe N, Doh M, Simakova O, Kurganov B, De Maio A (2004) Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. Faseb J 18(14):1636–1645. https://doi.org/10.1096/fj.04-2088com
Asea A, Rehli M, Kabingu E, Boch JA, Baré O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4*. J Biol Chem 277(17):15028–15034. https://doi.org/10.1074/jbc.M200497200
Bae J, Munshi A, Li C, Samur M, Prabhala R, Mitsiades C, Anderson KC, Munshi NC (2013) Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells. J Immunol (Baltimore, MD: 1950) 190(3):1360–1371. https://doi.org/10.4049/jimmunol.1200593
Berthenet K, Boudesco C, Collura A, Svrcek M, Richaud S, Hammann A, Causse S, Yousfi N, Wanherdrick K, Duplomb L, Duval A, Garrido C, Jego G (2016) Extracellular HSP110 skews macrophage polarization in colorectal cancer. Oncoimmunology 5(7):e1170264–e1170264. https://doi.org/10.1080/2162402X.2016.1170264
Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria NS, Basu S, Udono H, Srivastava PK (1997) Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 186(8):1315–1322. https://doi.org/10.1084/jem.186.8.1315
Broemer M, Krappmann D, Scheidereit C (2004) Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation. Oncogene 23(31):5378–5386. https://doi.org/10.1038/sj.onc.1207705
Chaumonnot K, Masson S, Sikner H, Bouchard A, Baverel V, Bellaye P-S, Collin B, Garrido C, Kohli E (2021) The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress. Cell Death Dis 12(1):114. https://doi.org/10.1038/s41419-020-03288-x
Chen H, Wu Y, Zhang Y, Jin L, Luo L, Xue B, Lu C, Zhang X, Yin Z (2006) Hsp70 inhibits lipopolysaccharide-induced NF-κB activation by interacting with TRAF6 and inhibiting its ubiquitination. FEBS Letters 580(13):3145–3152. https://doi.org/10.1016/j.febslet.2006.04.066
Chen Y-Q, Li P-C, Pan N, Gao R, Wen Z-F, Zhang T-Y, Huang F, Wu F-Y, Ou X-L, Zhang J-P, Zhu X-J, Hu H-M, Chen K, Cai Y-L, Wang L-X (2019) Tumor-released autophagosomes induces CD4 T cell-mediated immunosuppression via a TLR2–IL-6 cascade. J ImmunoTherapy Cancer 7(1):178. https://doi.org/10.1186/s40425-019-0646-5
Chen L, Zheng H, Yu X, Liu L, Li H, Zhu H, Zhang Z, Lei P, Shen G (2020) Tumor-secreted GRP78 promotes the establishment of a pre-metastatic niche in the liver microenvironment. Front Immunol 11(2544). https://doi.org/10.3389/fimmu.2020.584458
Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10(2):86–103. https://doi.org/10.1379/csc-99r.1
Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118(Pt 16):3631–3638. https://doi.org/10.1242/jcs.02494
Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, Mor F, Carmi P, Zanin-Zhorov A, Lider O, Cohen IR (2005) Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway. J Immunol 175(6):3594. https://doi.org/10.4049/jimmunol.175.6.3594
Cook KL, Soto-Pantoja DR, Clarke PAG, Cruz MI, Zwart A, Wärri A, Hilakivi-Clarke L, Roberts DD, Clarke R (2016) Endoplasmic reticulum stress protein GRP78 modulates lipid metabolism to control drug sensitivity and antitumor immunity in breast cancer. Cancer Res 76(19):5657. https://doi.org/10.1158/0008-5472.CAN-15-2616
Corrigall VM, Bodman-Smith MD, Brunst M, Cornell H, Panayi GS (2004) Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: Relevance to the treatment of inflammatory arthritis. Arthr Rheumat 50(4):1164–1171. https://doi.org/10.1002/art.20134
Dadey DYA, Kapoor V, Hoye K, Khudanyan A, Collins A, Thotala D, Hallahan DE (2017) Antibody targeting GRP78 enhances the efficacy of radiation therapy in human glioblastoma and non–small cell lung cancer cell lines and tumor models. Clin Cancer Res 23(10):2556. https://doi.org/10.1158/1078-0432.CCR-16-1935
Deffit SN, Blum JS (2015) Macronutrient deprivation modulates antigen trafficking and immune recognition through HSC70 accessibility. J Immunol (Baltimore, MD: 1950) 194(4):1446–1453. https://doi.org/10.4049/jimmunol.1402472
Doody ADH, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG, Adler AJ (2004) Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J Immunol (Baltimore, MD: 1950) 172(10):6087–6092. https://doi.org/10.4049/jimmunol.172.10.6087
Feng H, Zeng Y, Graner MW, Katsanis E (2002) Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells. Blood 100(12):4108–4115. https://doi.org/10.1182/blood-2002-05-1389
Figueiredo C, Wittmann M, Wang D, Dressel R, Seltsam A, Blasczyk R, Eiz-Vesper B (2009) Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells. Blood 113(13):3008–3016. https://doi.org/10.1182/blood-2008-06-162727
Flohé SB, Brüggemann J, Lendemans S, Nikulina M, Meierhoff G, Flohé S, Kolb H (2003) Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol 170(5):2340. https://doi.org/10.4049/jimmunol.170.5.2340
Flynn GC, Pohl J, Flocco MT, Rothman JE (1991) Peptide-binding specificity of the molecular chaperone BiP. Nature 353(6346):726–730. https://doi.org/10.1038/353726a0
Furuta K, Eguchi T (2021) Roles of HSP on antigen presentation. In: Asea AAA, Kaur P (eds) Heat shock proteins in human diseases. Springer International Publishing, Cham, pp 275–280. https://doi.org/10.1007/7515_2020_5
Gabai VL, Mabuchi K, Mosser DD, Sherman MY (2002) Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22(10):3415–3424. https://doi.org/10.1128/mcb.22.10.3415-3424.2002
Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G (2004) The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells. J Immunol 172(2):972. https://doi.org/10.4049/jimmunol.172.2.972
Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65(12):5238–5247. https://doi.org/10.1158/0008-5472.Can-04-3804
Gehrmann M, Liebisch G, Schmitz G, Anderson R, Steinem C, De Maio A, Pockley G, Multhoff G (2008) Tumor-specific Hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3. PLoS One 3(4):e1925. https://doi.org/10.1371/journal.pone.0001925
Gehrmann M, Cervello M, Montalto G, Cappello F, Gulino A, Knape C, Specht HM, Multhoff G (2014) Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Front Immunol 5(307). https://doi.org/10.3389/fimmu.2014.00307
Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini J-L, Schlemmer F, Tasdemir E, Uhl M, Génin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, André F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med 15(10):1170–1178. https://doi.org/10.1038/nm.2028
Gomez CR (2019) Hsp60 in cancer immunity: biological basis, diagnostic potential and therapeutic opportunities. In: Asea AAA, Kaur P (eds) Heat shock protein 60 in human diseases and disorders. Springer International Publishing, Cham, pp 117–134. https://doi.org/10.1007/978-3-030-23154-5_9
Gonzalez-Gronow M, Cuchacovich M, Llanos C, Urzua C, Gawdi G, Pizzo SV (2006) Prostate cancer cell proliferation is modulated by antibodies against glucose-regulated protein 78 isolated from patient serum. Cancer Res 66(23):11424. https://doi.org/10.1158/0008-5472.CAN-06-1721
Graner MW (2016) Chapter eight – HSP90 and immune modulation in cancer. In: Isaacs J, Whitesell L (eds) Advances in cancer research, vol 129. Academic Press, pp 191–224. https://doi.org/10.1016/bs.acr.2015.10.001
Hua Y, Yang Y, Sun S, Iwanowycz S, Westwater C, Reizis B, Li Z, Liu B (2017) Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c+ cells. Sci Reports 7(1):2171. https://doi.org/10.1038/s41598-017-02415-7
Ichiyanagi T, Imai T, Kajiwara C, Mizukami S, Nakai A, Nakayama T, Udono H (2010) Essential role of endogenous heat shock protein 90 of dendritic cells in antigen cross-presentation. J Immunol 185(5):2693. https://doi.org/10.4049/jimmunol.1000821
Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 88(2):232–238. https://doi.org/10.1002/1097-0215(20001015)88:2<232::AID-IJC14>3.0.CO;2-8
Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111. https://doi.org/10.1007/s12192-008-0068-7
Kant Misra U, Gonzalez-Gronow M, Gawdi G, Wang F, Vincent Pizzo S (2004) A novel receptor function for the heat shock protein Grp78: silencing of Grp78 gene expression attenuates α2M*-induced signalling. Cell Signal 16(8):929–938. https://doi.org/10.1016/j.cellsig.2004.01.003
Kocsis J, Madaras B, Tóth ÉK, Füst G, Prohászka Z (2010) Serum level of soluble 70-kD heat shock protein is associated with high mortality in patients with colorectal cancer without distant metastasis. Cell Stress Chaperones 15(2):143–151. https://doi.org/10.1007/s12192-009-0128-7
Kurotaki T, Tamura Y, Ueda G, Oura J, Kutomi G, Hirohashi Y, Sahara H, Torigoe T, Hiratsuka H, Sunakawa H, Hirata K, Sato N (2007) Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway. J Immunol 179(3):1803. https://doi.org/10.4049/jimmunol.179.3.1803
Lancaster GI, Febbraio MA (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280(24):23349–23355. https://doi.org/10.1074/jbc.M502017200
Laudanski K, De A, Miller-Graziano C (2007) Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells. Eur J Immunol 37(10):2812–2824. https://doi.org/10.1002/eji.200636993
Leo R, Johannes D, Inês CC, Valentina D, Manik C, Stefan K, Frank H, Andreas R, Hermann E, Max ST, Stephanie B (2015) GRP78-directed immunotherapy in relapsed or refractory multiple myeloma – results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6. Haematologica 100(3):377–384. https://doi.org/10.3324/haematol.2014.117945
Li R, Emsley J (2013) The organizing principle of the platelet glycoprotein Ib–IX–V complex. J Thrombosis Haemostasis 11(4):605–614. https://doi.org/10.1111/jth.12144
Li Y, Lu J, Cohen D, Prochownik EV (2008) Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα. Oncogene 27(11):1599–1609. https://doi.org/10.1038/sj.onc.1210794
Li H, Li Y, Liu D, Sun H, Su D, Yang F, Liu J (2013a) Extracellular HSP70/HSP70-PCs promote epithelial-mesenchymal transition of hepatocarcinoma cells. PLoS One 8(12):e84759. https://doi.org/10.1371/journal.pone.0084759
Li X, Liu Z, Yan X, Zhang X, Li Y, Zhao B, Wang S, Zhou X, Gao GF, Meng S (2013b) Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation. PLoS One 8(7):e68997. https://doi.org/10.1371/journal.pone.0068997
Lv L-H, Wan Y-L, Lin Y, Zhang W, Yang M, Li G-L, Lin H-M, Shang C-Z, Chen Y-J, Min J (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287(19):15874–15885. https://doi.org/10.1074/jbc.M112.340588
Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177(11):7849–7857. https://doi.org/10.4049/jimmunol.177.11.7849
Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43(3):168–175. https://doi.org/10.1016/j.ymeth.2007.06.009
Marcion G, Hermetet F, Neiers F, Uyanik B, Dondaine L, Dias AMM, Da Costa L, Moreau M, Bellaye P-S, Collin B, Gobbo J, Briand L, Seigneuric R, Kitten O, Cinier M, Garrido C (2021) Nanofitins targeting heat shock protein 110: An innovative immunotherapeutic modality in cancer. Int J Cancer 148(12):3019–3031. https://doi.org/10.1002/ijc.33485
Martine P, Chevriaux A, Derangère V, Apetoh L, Garrido C, Ghiringhelli F, Rébé C (2019) HSP70 is a negative regulator of NLRP3 inflammasome activation. Cell Death Dis 10(4):256. https://doi.org/10.1038/s41419-019-1491-7
Mbofung RM, McKenzie JA, Malu S, Zhang M, Peng W, Liu C, Kuiatse I, Tieu T, Williams L, Devi S, Ashkin E, Xu C, Huang L, Zhang M, Talukder AH, Tripathi SC, Khong H, Satani N, Muller FL, Roszik J, Heffernan T, Allison JP, Lizee G, Hanash SM, Proia D, Amaria R, Davis RE, Hwu P (2017) HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat Commun 8(1):451–451. https://doi.org/10.1038/s41467-017-00449-z
Misra UK, Gonzalez-Gronow M, Gawdi G, Pizzo SV (2005) The role of MTJ-1 in cell surface translocation of GRP78, a receptor for α2-macroglobulin-dependent signaling. J Immunol 174(4):2092–2097. https://doi.org/10.4049/jimmunol.174.4.2092
Morales C, Rachidi S, Hong F, Sun S, Ouyang X, Wallace C, Zhang Y, Garret-Mayer E, Wu J, Liu B, Li Z (2014) Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res 74(2):446. https://doi.org/10.1158/0008-5472.CAN-13-1677
Multhoff G, Hightower LE (1996) Cell surface expression of heat shock proteins and the immune response. Cell Stress Chaperones 1(3):167–176. https://doi.org/10.1379/1466-1268(1996)001<0167:cseohs>2.3.co;2
Multhoff G, Botzler C, Jennen L, Schmidt J, Ellwart J, Issels R (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158(9):4341
Multhoff G, Mizzen L, Winchester CC, Milner CM, Wenk S, Eissner G, Kampinga HH, Laumbacher B, Johnson J (1999) Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 27(11):1627–1636. https://doi.org/10.1016/s0301-472x(99)00104-6
Multhoff G, Pfister K, Gehrmann M, Hantschel M, Gross C, Hafner M, Hiddemann W (2001) A 14-mer Hsp70 peptide stimulates natural killer (NK) cell activity. Cell Stress Chaperones 6(4):337–344. https://doi.org/10.1379/1466-1268(2001)006<0337:AMHPSN>2.0.CO;2
Nizami S, Arunasalam K, Green J, Cook J, Lawrence CB, Zarganes-Tzitzikas T, Davis JB, Di Daniel E, Brough D (2021) Inhibition of the NLRP3 inflammasome by HSP90 inhibitors. Immunology 162(1):84–91. https://doi.org/10.1111/imm.13267
Quintana FJ, Cohen IR (2011) The HSP60 immune system network. Trends Immunol 32(2):89–95. https://doi.org/10.1016/j.it.2010.11.001
Quintana FJ, Mimran A, Carmi P, Mor F, Cohen IR (2008) HSP60 as a target of anti-ergotypic regulatory T cells. PLoS One 3(12):e4026. https://doi.org/10.1371/journal.pone.0004026
Raiter A, Lipovetzki J, Lubin I, Yerushalmi R (2020) GRP78 expression in peripheral blood mononuclear cells is a new predictive marker for the benefit of taxanes in breast cancer neoadjuvant treatment. BMC Cancer 20(1):333. https://doi.org/10.1186/s12885-020-06835-z
Rajagopal D, Bal V, Mayor S, George A, Rath S (2006) A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules. Eur J Immunol 36(4):828–841. https://doi.org/10.1002/eji.200535326
Rao A, Taylor JL, Chi-Sabins N, Kawabe M, Gooding WE, Storkus WJ (2012) Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells. Cancer Res 72(13):3196–3206. https://doi.org/10.1158/0008-5472.CAN-12-0538
Rondas D, Crèvecoeur I, D’Hertog W, Ferreira GB, Staes A, Garg AD, Eizirik DL, Agostinis P, Gevaert K, Overbergh L, Mathieu C (2014) Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes 64(2):573–586. https://doi.org/10.2337/db14-0621
Rosenzweig R, Nillegoda NB, Mayer MP, Bukau B (2019) The Hsp70 chaperone network. Nat Rev Mol Cell Biol 20(11):665–680. https://doi.org/10.1038/s41580-019-0133-3
Schopf FH, Biebl MM, Buchner J (2017) The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 18(6):345–360. https://doi.org/10.1038/nrm.2017.20
Seclì L, Fusella F, Avalle L, Brancaccio M (2021) The dark-side of the outside: how extracellular heat shock proteins promote cancer. Cell Mol Life Sci: CMLS 78(9):4069–4083. https://doi.org/10.1007/s00018-021-03764-3
Sedlacek AL, Kinner-Bibeau LB, Binder RJ (2016) Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity. Sci Rep 6(1):29889. https://doi.org/10.1038/srep29889
Seignez A, Joly A-L, Chaumonnot K, Hazoumé A, Sanka M, Marcion G, Boudesco C, Hammann A, Seigneuric R, Jégo G, Ducoroy P, Delarue P, Senet P, Castilla-Llorente C, Solary E, Durey M-A, Rubio M-T, Hermine O, Kohli E, Garrido C (2017) Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease. JCI Insight 2(6). https://doi.org/10.1172/jci.insight.90531
Shevtsov M, Pitkin E, Ischenko A, Stangl S, Khachatryan W, Galibin O, Edmond S, Lobinger D, Multhoff G (2019) Ex vivo Hsp70-activated NK cells in combination with PD-1 inhibition significantly increase overall survival in preclinical models of glioblastoma and lung cancer. Front Immunol 10:454–454. https://doi.org/10.3389/fimmu.2019.00454
Shimp SK, Parson CD, Regna NL, Thomas AN, Chafin CB, Reilly CM, Nichole Rylander M (2012) HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways. Inflam Res 61(5):521–533. https://doi.org/10.1007/s00011-012-0442-x
Shinagawa N, Yamazaki K, Tamura Y, Imai A, Kikuchi E, Yokouchi H, Hommura F, Oizumi S, Nishimura M (2008) Immunotherapy with dendritic cells pulsed with tumor-derived gp96 against murine lung cancer is effective through immune response of CD8+ cytotoxic T lymphocytes and natural killer cells. Cancer Immunol Immunotherapy 57(2):165–174. https://doi.org/10.1007/s00262-007-0359-3
Singh-Jasuja H, Scherer HU, Hilf N, Arnold-Schild D, Rammensee H-G, Toes REM, Schild H (2000) The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur J Immunol 30(8):2211–2215. https://doi.org/10.1002/1521-4141(2000)30:8<2211::AID-IMMU2211>3.0.CO;2-0
Soto-Pantoja DR, Wilson AS, Clear KYJ, Westwood B, Triozzi PL, Cook KL (2017) Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness. Oncotarget 8(46)
Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425. https://doi.org/10.1146/annurev.immunol.20.100301.064801
Suzuki K, Ito Y, Wakai K, Kawado M, Hashimoto S, Seki N, Ando M, Nishino Y, Kondo T, Watanabe Y, Ozasa K, Inoue T, Tamakoshi A (2006) Serum heat shock protein 70 levels and lung cancer risk: a case-control study nested in a large cohort study. Cancer Epidemiol Biomark Prev 15(9):1733. https://doi.org/10.1158/1055-9965.EPI-06-0005
Swanson KV, Deng M, Ting JPY (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19(8):477–489. https://doi.org/10.1038/s41577-019-0165-0
Taha EA, Ono K, Eguchi T (2019) Roles of extracellular HSPs as biomarkers in immune surveillance and immune evasion. Int J Mol Sci 20(18):4588
Tang Y, Jiang Q, Ou Y, Zhang F, Qing K, Sun Y, Lu W, Zhu H, Gong F, Lei P, Shen G (2016) BIP induces mice CD19hi regulatory B cells producing IL-10 and highly expressing PD-L1, FasL. Mol Immunol 69:44–51. https://doi.org/10.1016/j.molimm.2015.10.017
Tang X, Chang C, Guo J, Lincoln V, Liang C, Chen M, Woodley DT, Li W (2019) Tumour-secreted hsp90α on external surface of exosomes mediates tumour – stromal cell communication via autocrine and paracrine mechanisms. Sci Rep 9(1):15108–15108. https://doi.org/10.1038/s41598-019-51704-w
Udono H, Srivastava PK (1994) Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol 152(11):5398
Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E (1986) A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc Natl Acad Sci USA 83(10):3121–3125. https://doi.org/10.1073/pnas.83.10.3121
Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Häcker H, Wagner H (2001) Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells*. J Biol Chem 276(33):31332–31339. https://doi.org/10.1074/jbc.M103217200
Vig S, Buitinga M, Rondas D, Crèvecoeur I, van Zandvoort M, Waelkens E, Eizirik DL, Gysemans C, Baatsen P, Mathieu C, Overbergh L (2019) Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells. Cell Death Dis 10(4):309. https://doi.org/10.1038/s41419-019-1518-0
Wachstein J, Tischer S, Figueiredo C, Limbourg A, Falk C, Immenschuh S, Blasczyk R, Eiz-Vesper B (2012) HSP70 enhances immunosuppressive function of CD4+CD25+FoxP3+ T regulatory cells and cytotoxicity in CD4+CD25− T cells. PLoS One 7(12):e51747. https://doi.org/10.1371/journal.pone.0051747
Wang X-Y, Kazim L, Repasky EA, Subjeck JR (2001) Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol 166(1):490. https://doi.org/10.4049/jimmunol.166.1.490
Wang X-Y, Kazim L, Repasky EA, Subjeck JR (2003) Immunization with tumor-derived ER chaperone grp170 elicits tumor-specific CD8+ T-cell responses and reduces pulmonary metastatic disease. Int J Cancer 105(2):226–231. https://doi.org/10.1002/ijc.11058
Wang X-Y, Arnouk H, Chen X, Kazim L, Repasky EA, Subjeck JR (2006) Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J Immunol 177(3):1543. https://doi.org/10.4049/jimmunol.177.3.1543
Wang H, Yu X, Guo C, Zuo D, Fisher PB, Subjeck JR, Wang X-Y (2013) Enhanced endoplasmic reticulum entry of tumor antigen is crucial for cross-presentation induced by dendritic cell-targeted vaccination. J Immunol (Baltimore, MD: 1950) 191(12):6010–6021. https://doi.org/10.4049/jimmunol.1302312
Wang H, Pezeshki AM, Yu X, Guo C, Subjeck JR, Wang X-Y (2015) The endoplasmic reticulum chaperone GRP170: from immunobiology to cancer therapeutics. Front Oncol 4(377). https://doi.org/10.3389/fonc.2014.00377
Wang L, Fu Y, Yu B, Jiang X, Liu H, Liu J, Zha B, Chu Y (2021) HSP70, a novel regulatory molecule in B cell-mediated suppression of autoimmune diseases. J Mol Biol 433(1):166634. https://doi.org/10.1016/j.jmb.2020.08.019
Weng D, Calderwood SK, Gong J (2011) Preparation of a heat-shock protein 70-based vaccine from DC-tumor fusion cells. Methods Mol Biol 787:255–265. https://doi.org/10.1007/978-1-61779-295-3_19
Wu BX, Hong F, Zhang Y, Ansa-Addo E, Li Z (2016) Chapter seven – GRP94/gp96 in cancer: biology, structure, immunology, and drug development. In: Isaacs J, Whitesell L (eds) Advances in cancer research, vol 129. Academic Press, pp 165–190. https://doi.org/10.1016/bs.acr.2015.09.001
Xie Y, Bai O, Zhang H, Yuan J, Zong S, Chibbar R, Slattery K, Qureshi M, Wei Y, Deng Y, Xiang J (2010) Membrane-bound HSP70-engineered myeloma cell-derived exosomes stimulate more efficient CD8(+) CTL- and NK-mediated antitumour immunity than exosomes released from heat-shocked tumour cells expressing cytoplasmic HSP70. J Cell Mol Med 14(11):2655–2666. https://doi.org/10.1111/j.1582-4934.2009.00851.x
Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrançois L, Li Z (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26(2):215–226. https://doi.org/10.1016/j.immuni.2006.12.005
Yang H-Z, Cui B, Liu H-Z, Mi S, Yan J, Yan H-M, Hua F, Lin H, Cai W-F, Xie W-J, Lv X-X, Wang X-X, Xin B-M, Zhan Q-M, Hu Z-W (2009) Blocking TLR2 activity attenuates pulmonary metastases of tumor. PLoS One 4(8):e6520. https://doi.org/10.1371/journal.pone.0006520
Yang M, Zhang F, Qin K, Wu M, Li H, Zhu H, Ning Q, Lei P, Shen G (2016) Glucose-regulated protein 78-induced myeloid antigen-presenting cells maintained tolerogenic signature upon LPS stimulation. Front Immunol 7:552–552. https://doi.org/10.3389/fimmu.2016.00552
Zanin-Zhorov A, Bruck R, Tal G, Oren S, Aeed H, Hershkoviz R, Cohen IR, Lider O (2005) Heat shock protein 60 inhibits Th1-mediated hepatitis model via innate regulation of Th1/Th2 transcription factors and cytokines. J Immunol 174(6):3227. https://doi.org/10.4049/jimmunol.174.6.3227
Zavareh RB, Spangenberg SH, Woods A, MartÃnez-Peña F, Lairson LL (2021) HSP90 inhibition enhances cancer immunotherapy by modulating the surface expression of multiple immune checkpoint proteins. Cell Chem Biol 28(2):158–168.e155. https://doi.org/10.1016/j.chembiol.2020.10.005
Zhang Y, Wu BX, Metelli A, Thaxton JE, Hong F, Rachidi S, Ansa-Addo E, Sun S, Vasu C, Yang Y, Liu B, Li Z (2015) GP96 is a GARP chaperone and controls regulatory T cell functions. J Clin Invest 125(2):859–869. https://doi.org/10.1172/JCI79014
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this entry
Cite this entry
Albakova, Z. (2022). Heat Shock Proteins in Tumor Immunology. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_30-1
Download citation
DOI: https://doi.org/10.1007/978-3-030-80962-1_30-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-80962-1
Online ISBN: 978-3-030-80962-1
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences