Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Chronic lymphocytic leukemia

PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia

Leukemia volume 34, pages 451–461 (2020)Cite this article

Subjects

Abstract

Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Burger JA, O’Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nat. Rev. Clin Oncol. 2018;15:510–27.

    Article  CAS  Google Scholar 

  2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745–60.

    Article  CAS  Google Scholar 

  3. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. New Engl J Med. 2016;374:311–22.

    Article  CAS  Google Scholar 

  4. Morabito F, Gentile M, Seymour JF, Polliack A Ibrutinib, idelalisib and obinutuzumab for the treatment of patients with chronic lymphocytic leukemia: three new arrows aiming at the target. Leuk Lymphoma. 2015;56:3250–6.

  5. Killock D. Venetoclax-rituximab holds substantial promise in CLL. Nat Rev Clin Oncol. 2018;15:344–5.

    CAS  PubMed  Google Scholar 

  6. Owen CJ, Stewart DA. Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective. Ther Adv Hematol. 2015;6:161–70.

    Article  CAS  Google Scholar 

  7. GauNLC S, Fatehchand K, Elavazhagan S, Reader BF, Ren L, Mo X, et al. Reprogramming nurse-like cells with interferon gamma to interrupt chronic lymphocytic leukemia cell survival. J Biol Chem. 2016;291:14356–62.

    Article  Google Scholar 

  8. Galletti G, Scielzo C, Barbaglio F, Rodriguez TV, Riba M, Lazarevic D, et al. Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression. Cell Rep. 2016;14:1748–60.

    Article  CAS  Google Scholar 

  9. Boissard F, Laurent C, Ramsay AG, Quillet-Mary A, Fournie JJ, Poupot M, et al. Nurse-like cells impact on disease progression in chronic lymphocytic leukemia. Blood Cancer J. 2016;6:1–4.

  10. Chen YCE, Mapp S, Blumenthal A, Burgess ML, Mazzieri R, Mattarollo SR, et al. The duality of macrophage function in chronic lymphocytic leukaemia. Bba-Rev Cancer. 2017;1868:176–82.

    CAS  Google Scholar 

  11. Hanna BS, McClanahan F, Yazdanparast H, Zaborsky N, Kalter V, Rossner PM, et al. Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo. Leukemia. 2016;30:570–9.

    Article  CAS  Google Scholar 

  12. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell’Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000;96:2655–63.

    Article  CAS  Google Scholar 

  13. Church AK, VanDerMeid KR, Baig NA, Baran AM, Witzig TE, Nowakowski GS, et al. Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages. Clin Exp Immunol. 2016;183:90–101.

    Article  CAS  Google Scholar 

  14. Weiner LM, Surana R, Wang SZ. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10:317–27.

    Article  CAS  Google Scholar 

  15. Herter S, Birk MC, Klein C, Gerdes C, Umana P, Bacac M. Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity. J Immunol. 2014;192:2252–60.

    Article  CAS  Google Scholar 

  16. Elias S, Kahlon S, Kotzur R, Kaynan N, Mandelboim O. Obinutuzumab activates FcgammaRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL). Oncoimmunology 2018;7:e1428158.

    Article  Google Scholar 

  17. Stewart R, Hammond SA, Oberst M, Wilkinson RW. The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer. J Immunother Cancer. 2014;2:29–39.

  18. Burgess M, Mapp S, Mazzieri R, Cheung C, Chambers L, Mattarollo SR, et al. Increased FcgammaRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients. Oncogene. 2017;36:2366–76.

    Article  CAS  Google Scholar 

  19. Yu CH, Micaroni M, Puyskens A, Schultz TE, Yeo JC, Stanley AC, et al. RP105 engages phosphatidylinositol 3-Kinase p110delta To facilitate the trafficking and secretion of cytokines in macrophages during mycobacterial infection. J Immunol. 2015;195:3890–900.

    Article  CAS  Google Scholar 

  20. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol. 2016;16:702–14.

    Article  CAS  Google Scholar 

  21. So L, Fruman DA. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem J. 2012;442:465–81.

    Article  CAS  Google Scholar 

  22. Wall AA, Luo L, Hung Y, Tong SJ, Condon ND, Blumenthal A, et al. Small GTPase Rab8a-recruited phosphatidylinositol 3-Kinase gamma regulates signaling and cytokine outputs from endosomal toll-like receptors. J Biol Chem. 2017;292:4411–22.

    Article  CAS  Google Scholar 

  23. Low PC, Misaki R, Schroder K, Stanley AC, Sweet MJ, Teasdale RD, et al. Phosphoinositide 3-kinase delta regulates membrane fission of Golgi carriers for selective cytokine secretion. J Cell Biol. 2010;190:1053–65.

    Article  CAS  Google Scholar 

  24. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature. 2016;539:437–42.

    Article  CAS  Google Scholar 

  25. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Hirschhorn-Cymerman D, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539:443–7.

  26. VanDerMeid KR, Elliott MR, Baran AM, Barr PM, Chu CC, Zent CS. Cellular cytotoxicity of next-generation CD20 monoclonal antibodies. cancer immunology. Research. 2018;6:1150–60.

    CAS  Google Scholar 

  27. Saenz-Ponce N, Pillay R, de Long LM, Kashyap T, Argueta C, Landesman Y, et al. Targeting the XPO1-dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas. Sci Transl Med. 2018;10:1–12.

  28. Burgess M, Gill D, Singhania R, Cheung C, Chambers L, Renyolds BA, et al. CD62L as a therapeutic target in chronic lymphocytic leukemia. Clin Cancer Res. 2013;19:5675–85.

    Article  CAS  Google Scholar 

  29. Roghanian A, Teige I, Martensson L, Cox KL, Kovacek M, Ljungars A, et al. Antagonistic human FcgammaRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo. Cancer Cell. 2015;27:473–88.

    Article  CAS  Google Scholar 

  30. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. New Engl J Med. 2014;370:997–1007.

    Article  CAS  Google Scholar 

  31. Goulielmaki E, Bermudez-Brito M, Andreou M, Tzenaki N, Tzardi M, de Bree E, et al. Pharmacological inactivation of the PI3K p110delta prevents breast tumour progression by targeting cancer cells and macrophages. Cell Death Dis. 2018;9:678.

    Article  Google Scholar 

  32. Velez NF, Karia PS, Vartanov AR, Davids MS, Brown JR, Schmults CD. Association of advanced leukemic stage and skin cancer tumor stage with poor skin cancer outcomes in patients with chronic lymphocytic leukemia. Jama Dermatol. 2014;150:280–7.

    Article  Google Scholar 

  33. Mansfield AS, Rabe KG, Slager SL, Schwager SM, Call TG, Brewer JD, et al. Skin cancer surveillance and malignancies of the skin in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia. J Oncol Pract. 2014;10:E1–4.

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the generosity of the patients who donated their time and blood for this study.

Author information

Authors and Affiliations

  1. University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia

    Yu-Chen Enya Chen, Melinda Burgess, Antje Blumenthal & Nicholas A. Saunders

  2. Department of Haematology, Cancer Services Unit, Princess Alexandra Hospital, Woolloongabba, QLD, Australia

    Melinda Burgess, Sally Mapp, Peter Mollee & Devinder Gill

Authors
  1. Yu-Chen Enya Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melinda Burgess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sally Mapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Mollee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Devinder Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antje Blumenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicholas A. Saunders
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas A. Saunders.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Enya Chen, YC., Burgess, M., Mapp, S. et al. PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia. Leukemia 34, 451–461 (2020). https://doi.org/10.1038/s41375-019-0556-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0556-z

This article is cited by

Search

Advanced search

Quick links