Frontiers reaches 6.4 on Journal Impact Factors

Editorial ARTICLE

Front. Oncol., 17 November 2015 | https://doi.org/10.3389/fonc.2015.00252

Editorial: Endoplasmic Reticulum and Its Role in Tumor Immunity

  • 1University of Exeter Medical School, Exeter, UK
  • 2Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
  • 3Laboratory for Translational Surgical Oncology, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

Cancer cells express surface proteins and display antigens that differ from the “norm.” These differences can be exploited to promote a therapeutic antitumor immune response. Specifically, components within the endoplasmic reticulum (ER) play a critical role in deciding which antigenic peptides are presented on the cancer cell surface to immune cells. Furthermore, under stress conditions, certain ER-resident proteins can exit the ER and translocate to the surface. The translocation of such ER proteins to the outside of the cell (1, 2) can lead to modulation of immune responses in cancer (3, 4), autoimmunity (5) and other diseases (6, 7). Normally, proteins undergo a number of ER stress checks for correct folding and, e.g., ability to resist inappropriate oxidation and reduction before secretion. Failing these quality controls leads to ER stress and triggers a series of unfolded protein responses (UPRs) to restore order. In cancer cells, these pathways can be dysregulated opening up the possibility of developing potential therapeutics to target cancer cells (8). In this topic, these various aspects of the ER in tumor immunity are explored in a series of focused review and research articles.

Behind the “Ion” Curtain

Within the Ca2+-ion rich confines of the ER, chaperones, oxidoreductases, aminopeptidases (ERAPs) work industriously for the benefit of the cellular state, regulating signaling to the “outside world.” The calcium channels linking the ER lumen and cytosol act as ER stress gates and chaperones, such as GRP78, act as gate keepers deciding the fate of the cell by their ability to control Ca2+ release (9). Alterations in Ca2+ homeostasis in the ER can provoke cell stress and trigger one or more UPR coping mechanism pathways, which normally leads to either recovery of a stressed cell or non-inflammatory cell death. However, solid tumors typically thrive in a low oxygen and nutrient environment that usually triggers ER stress. Dicks and coworkers describe corrective UPR strategies that aid malignant cells to survive in this environment, with a focus on GRP78 (10). In brief, GRP78 transcription triggered by ER stress facilitates chromatin remodeling and DNA damage repair and in certain types of malignancies aids survival.

One of the best known immune-regulatory functions occurring within the ER is the assembly of the major histocompatibility complex (MHC)-I/antigen peptide complex. Stratikos and colleagues report on the role of the ER aminopeptidases (ERAP1 and 2) in generating mature antigenic epitopes for loading onto the MHC class I molecules, prior to their transport to the cell surface (11). The authors suggest that both ERAP 1/2 are required for natural killer and T cell-mediated immunity against tumors. These highly polymorphic ERAPs contain many single nucleotide polymorphisms (SNPs) associated with diseases, including cancer (12). These SNPs can influence aminopeptidase expression, enzymatic activity, and antitumor cytokine expression. Such ERAP mutations may aid tumor cells to avoid immune surveillance and eradication (13).

The Great Escape

Endoplasmic reticulum chaperones and oxidoreductases can serve as “eat-me” signals on the surface of tumors cells, while promoting tumor growth on others. How ER chaperones escape retention from the ER and move to the plasma membrane remains contentious (14). Several articles within this e-book describe mechanisms to prevent and allow escape of chaperones from the ER and how this influences tumor recognition. Gutiérrez and Simmen describe the regulatory processes involved in retaining or recapturing ER proteins as they attempt to leave the ER (15). Gutiérrez and Simmen describe the conditions by which ER chaperones and oxidoreductases (calreticulin, ERp57, PDI, and GRP94) escape retention and enhance tumor elimination by the immune system. Conversely, other ER proteins (BiP/GRP78) are expressed on many cancer cell surfaces and enhance proliferation, angiogenesis, and therapeutic resistance (16). Undoubtedly, if the “escape” and retention of ER proteins to and from the cell surface can be controlled, the process could be exploited for specific cancer therapies. However, methods to trigger escape of potentially immunogenic regulatory proteins from the ER will have to be strictly regulated, given their ability to modulate tumor growth and induce unwanted adaptive immunity in other diseases. Wiersma and coworkers (5) highlight the fact that in autoimmune diseases, cell stress provokes extracellular release of some ER proteins, which can affect innate and adaptive immune systems and trigger inflammation (1719).

The idiom “That which hath been is now; and that which is to be hath already been” (King James Bible, Ecclesiastes 3:15) is no better illustrated by the fact that parasites have been secreting chaperones for thousands of years as a defense mechanism against the human immune system (20, 21). Ramirez-Toloza et al. (22) describe how surface calreticulin on the Chagas disease causing parasite Trypanosoma cruzi blocks activation of complement and aids immune escape of the parasite. Moreover, people with Chagas disease appear less susceptible to certain malignancies (23), and Ramirez-Toloza et al. identify segments of calreticulin that can inhibit tumor angiogenesis.

War and Peace

Several papers in this e-book describe immune properties of ER proteins capable of raging “war” against tumors. Wang and colleagues describe the adjuvant properties of the stress inducible glucose-regulated protein 170 (GRP170). Previously, they showed an isoform of GRP170 was secreted in melanoma, prostate, and colorectal cancer cells (2426). GRP170 associates with tumor antigens both intracellularly and extracellularly, acting like a double agent, inducing potent anticancer immunity when outside the cells, but aiding the survival of cancer cells when within the ER. The authors have exploited GRP170 to develop an immune adjuvant for cancer vaccines to trigger a number of adaptive immune processes. An alternative means of delivering antitumor chaperones to the cell surface is by inducing cell stress using photodynamic therapy (PDT) to generate localized production of reactive oxygen species by transfer of light energy from the photosensitizer chlorin C6. This strategy induces surface exposure of calreticulin within minutes of treatment in squamous carcinoma cells (27). Tumoricidal activity is enhanced when PDT treated cells are supplemented with additional recombinant calreticulin. In a similar manner, de Bruyn and coworkers describe that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) recruits CRT to its TRAIL-receptor 2 DISC complex and dissociate CRT from CD47 on the cell surface of cancer cells (28), whereby it may or may not facilitate phagocytic uptake by dendritic cells.

A major aspect of ER protein stimulation of anticancer immunity is to activate specific cytotoxic T cells to provide long lasting immunity against developing tumors. Løset et al. illustrate how tumor-specific T cells armed with specific T-cell receptors (TCRs) could eradicate tumors by interacting with MHC class I containing tumor and/or chaperone peptides (29). Løset and coworkers highlight an alternative therapeutic approach that exploits soluble TCRs that engage peptide/MHC (pMHC) complexes, some of which are now in clinical trials. As an alternative to the stealth-like cancer eradication by TCR-transduced T cells, Graner and colleagues have proposed a more “blanket-bombing” approach. They describe the development of a vaccination rationale comprising of chaperone-rich cell lysates (CRCL) purified from solid tumors designed to induce a plethora of immune responses (30).

Summary

The ER and its specialized proteins do play a major role in tumor immunity both indirectly and directly. Clearly, there is much more to understand but the potential role and therapeutic options of ER proteins, as described herein, will aid further research into this fascinating topic.

Author Contributions

Dr. MM, Dr. PE, and Dr. EB have discussed/written the editorial content and approved it.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We are very grateful to all the authors who contributed to this topic and for the interest shown by the scientific community at large.

References

1. Tarr JM, Young PJ, Morse R, Shaw DJ, Haigh R, Petrov PG, et al. A mechanism of release of calreticulin from cells during apoptosis. J Mol Biol (2010) 401(5):799–812. doi: 10.1016/j.jmb.2010.06.064

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Kepp O, Gdoura A, Martins I, Panaretakis T, Schlemmer F, Tesniere A, et al. Lysyl tRNA synthetase is required for the translocation of calreticulin to the cell surface in immunogenic death. Cell Cycle (2010) 9(15):3072–7. doi:10.4161/cc.9.15.12459

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Kim H, Bhattacharya A, Qi L. Endoplasmic reticulum quality control in cancer: friend or foe. Semin Cancer Biol (2015) 33:25–33. doi:10.1016/j.semcancer.2015.02.003

CrossRef Full Text | Google Scholar

4. Wang WA, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta (2014) 1843(10):2143–9. doi:10.1016/j.bbamcr.2014.01.012

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Wiersma VR, Michalak M, Abdullah TM, Bremer E, Eggleton P. Mechanisms of translocation of ER chaperones to the cell surface and immunomodulatory roles in cancer and autoimmunity. Front Oncol (2015) 5:7. doi:10.3389/fonc.2015.00007

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Gold L, Williams D, Groenendyk J, Michalak M, Eggleton P. Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop. Cell Stress Chaperones (2015) 20(6):875–83. doi:10.1007/s12192-015-0638-4

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Eggleton P, Michalak M. Calreticulin for better or for worse, in sickness and in health, until death do us part. Cell Calcium (2013) 54(2):126–31. doi:10.1016/j.ceca.2013.05.006

CrossRef Full Text | Google Scholar

8. Kato H, Nishitoh H. Stress responses from the endoplasmic reticulum in cancer. Front Oncol (2015) 5:93. doi:10.3389/fonc.2015.00093

CrossRef Full Text | Google Scholar

9. Hammadi M, Oulidi A, Gackiere F, Katsogiannou M, Slomianny C, Roudbaraki M, et al. Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78. FASEB J (2013) 27(4):1600–9. doi:10.1096/fj.12-218875

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Dicks N, Gutierrez K, Michalak M, Bordignon V, Agellon LB. Endoplasmic reticulum stress, genome damage, and cancer. Front Oncol (2015) 5:11. doi:10.3389/fonc.2015.00011

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Stratikos E, Stamogiannos A, Zervoudi E, Fruci D. A role for naturally occurring alleles of endoplasmic reticulum aminopeptidases in tumor immunity and cancer pre-disposition. Front Oncol (2014) 4:363. doi:10.3389/fonc.2014.00363

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Fruci D, Romania P, D’Alicandro V, Locatelli F. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases. Tissue Antigens (2014) 84(2):177–86. doi:10.1111/tan.12410

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Mehta AM, Spaans VM, Mahendra NB, Osse EM, Vet JN, Purwoto G, et al. Differences in genetic variation in antigen-processing machinery components and association with cervical carcinoma risk in two Indonesian populations. Immunogenetics (2015) 67(5–6):267–75. doi:10.1007/s00251-015-0834-5

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Johnson S, Michalak M, Opas M, Eggleton P. The ins and outs of calreticulin: from the ER lumen to the extracellular space. Trends Cell Biol (2001) 11(3):122–9. doi:10.1016/S0962-8924(01)01926-2

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Gutierrez T, Simmen T. Endoplasmic reticulum chaperones and oxidoreductases: critical regulators of tumor cell survival and immunorecognition. Front Oncol (2014) 4:291. doi:10.3389/fonc.2014.00291

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer (2014) 14(4):263–76. doi:10.1038/nrc3701

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Tarr JM, Winyard PG, Ryan B, Harries LW, Haigh R, Viner N, et al. Extracellular calreticulin is present in the joints of patients with rheumatoid arthritis and inhibits FasL (CD95L)-mediated apoptosis of T cells. Arthritis Rheum (2010) 62(10):2919–29. doi:10.1002/art.27602

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Donnelly S, Roake W, Brown S, Young P, Naik H, Wordsworth P, et al. Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum (2006) 54(5):1543–56. doi:10.1002/art.21783

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Kovacs H, Campbell ID, Strong P, Johnson S, Ward FJ, Reid KB, et al. Evidence that C1q binds specifically to CH2-like immunoglobulin gamma motifs present in the autoantigen calreticulin and interferes with complement activation. Biochemistry (1998) 37(51):17865–74. doi:10.1021/bi973197p

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Kasper G, Brown A, Eberl M, Vallar L, Kieffer N, Berry C, et al. A calreticulin-like molecule from the human hookworm Necator americanus interacts with C1q and the cytoplasmic signalling domains of some integrins. Parasite Immunol (2001) 23(3):141–52. doi:10.1046/j.1365-3024.2001.00366.x

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Ferreira V, Valck C, Sanchez G, Gingras A, Tzima S, Molina MC, et al. The classical activation pathway of the human complement system is specifically inhibited by calreticulin from Trypanosoma cruzi. J Immunol (2004) 172(5):3042–50. doi:10.4049/jimmunol.172.5.3042

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Ramirez-Toloza G, Aguilar-Guzman L, Valck C, Abello P, Ferreira A. Is it all that bad when living with an intracellular protozoan? The role of Trypanosoma cruzi calreticulin in angiogenesis and tumor growth. Front Oncol (2014) 4:382. doi:10.3389/fonc.2014.00382

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Roskin G. Toxin therapy of experimental cancer; the influence of protozoan infections upon transplanted cancer. Cancer Res (1946) 6:363–5.

Google Scholar

24. Wang XY, Arnouk H, Chen X, Kazim L, Repasky EA, Subjeck JR. Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J Immunol (2006) 177(3):1543–51. doi:10.4049/jimmunol.177.3.1543

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Gao P, Sun X, Chen X, Subjeck J, Wang XY. Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. Cancer Immunol Immunother (2009) 58(8):1319–28. doi:10.1007/s00262-008-0647-6

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Arnouk H, Zynda ER, Wang XY, Hylander BL, Manjili MH, Repasky EA, et al. Tumour secreted grp170 chaperones full-length protein substrates and induces an adaptive anti-tumour immune response in vivo. Int J Hyperthermia (2010) 26(4):366–75. doi:10.3109/02656730903485910

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Korbelik M, Banath J, Saw KM, Zhang W, Ciplys E. Calreticulin as cancer treatment adjuvant: combination with photodynamic therapy and photodynamic therapy-generated vaccines. Front Oncol (2015) 5:15. doi:10.3389/fonc.2015.00015

PubMed Abstract | CrossRef Full Text | Google Scholar

28. de Bruyn M, Wiersma VR, Helfrich W, Eggleton P, Bremer E. The ever-expanding immunomodulatory role of calreticulin in cancer immunity. Front Oncol (2015) 5:35. doi:10.3389/fonc.2015.00035

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Loset GA, Berntzen G, Frigstad T, Pollmann S, Gunnarsen KS, Sandlie I. Phage display engineered T cell receptors as tools for the study of tumor peptide-MHC interactions. Front Oncol (2014) 4:378. doi:10.3389/fonc.2014.00378

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Graner MW, Lillehei KO, Katsanis E. Endoplasmic reticulum chaperones and their roles in the immunogenicity of cancer vaccines. Front Oncol (2014) 4:379. doi:10.3389/fonc.2014.00379

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: aminopeptidases, autoimmunity, angiogenesis, cancer, genome damage, oxidoreductases, phage display, vaccines

Citation: Eggleton P, Michalak M and Bremer E (2015) Editorial: Endoplasmic Reticulum and Its Role in Tumor Immunity. Front. Oncol. 5:252. doi: 10.3389/fonc.2015.00252

Received: 12 October 2015; Accepted: 30 October 2015;
Published: 17 November 2015

Edited and reviewed by: Catherine Sautes-Fridman, UMRS 1138, France

Copyright: © 2015 Eggleton, Michalak and Bremer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Paul Eggleton, p.eggleton@exeter.ac.uk