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.

  • Research Highlight
  • Published:

Immature and mature antibodies as defenders against cancer

Cellular & Molecular Immunology volume 20, pages 3–5 (2023)Cite this article

Subjects

Antibodies (Abs) are glycoprotein molecules that represent an essential component of the adaptative immune response. They are secreted in body fluids and act as a critical part of immune defense. Although recognition of self-antigens by Abs is normally selected against during B-cell development, autoreactive Abs can be generated as a result of pathological immune responses, as observed in autoimmune diseases. Autoantibodies can also be produced in cancer patients, where they may have beneficial roles [1]. Indeed, the presence of intratumoral antibody-secreting cells (ASCs) and B-cell-rich tertiary lymphoid structures (TLSs) has been observed in many cancer types and generally correlates with a favorable clinical prognosis [2,3,4,5,6]. The existence of specific antitumor antibody responses suggests that tumor cells express molecules that are recognized as nonself antigens by the immune system or that tolerance of self-antigens expressed on cancer cells is lost [1, 4]. The study of the origin of tumor-reactive Abs and their specificity and functions is of paramount importance for understanding the development of adaptive antitumor immune responses and for revealing novel therapeutic avenues. A recent publication in Cell by Mazor et al. [7] has provided an important advance in our understanding of antibody responses in cancer. In particular, this work paves the way for the distinction between antibody-reactive tumors and antibody-nonreactive tumors, which is reminiscent of the dichotomy of the noninfiltrated “cold” tumor microenvironment (TME) in contrast with the highly infiltrated with immune cells “hot” TME [8]. Moreover, an important finding of the study was the demonstration that tumor-directed autoreactivity may be either preexisting or induced by somatic hypermutations, a mechanism related to the chronicity of cancer.

In their study, Mazor et al. [7]. examined tumor samples from untreated high-grade serous ovarian cancer (HGSOC) patients. The samples were stained for IgG Abs, and by using a machine learning approach, the localization of IgG was analyzed by histology. The data showed that many HGSOC primary tumors had much higher levels of endogenous IgG deposits than healthy ovarian tissue (64 vs. 10%, respectively). The authors further confirmed this observation in live epithelial and metastatic cells using flow cytometry. Furthermore, after purification of polyclonal IgG Abs from tumor ascites, the binding of Abs to cancer cells was studied, and 72% of ascites contained IgG Abs specific for tumor cells. Importantly, using immunohistochemistry and flow cytometry analysis, the authors revealed that tumor samples had tertiary lymphoid structure (TLS)-like clusters with more than half of the intratumoral ASCs producing IgG1 Abs. These results imply that endogenous tumor-reactive Abs, probably produced by intratumoral ASCs, can bind the surface of ovarian cancer cells. The binding of endogenous Abs to tumor cells might be a frequent feature of antitumoral immune responses because it has also been found in several other types of cancers tested in the present study and other studies, particularly in renal and urothelial carcinoma [6, 7]. Importantly, Mazor et al. demonstrated that the presence of IgG-producing ASCs and deposits of IgG on the surface of tumor cells was associated with a significantly better prognosis for patients with HGSOC. These findings are in line with the positive impact of the presence of B-cell-containing TLSs observed in several cancers [4,5,6, 9, 10].

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

References

  1. Zaenker P, Gray ES, Ziman MR. Autoantibody production in cancer-the humoral immune response toward autologous antigens in cancer patients. Autoimmun Rev. 2016;15:477–83.

    Article  CAS  Google Scholar 

  2. Dieu-Nosjean MC, Giraldo NA, Kaplon H, Germain C, Fridman WH, Sautes-Fridman C. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev. 2016;271:260–75.

    Article  CAS  Google Scholar 

  3. Teillaud JL, Dieu-Nosjean MC. Tertiary lymphoid structures: an anti-tumor school for adaptive immune cells and an antibody factory to fight cancer? Front Immunol. 2017;8:830.

    Article  Google Scholar 

  4. Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol. 2020;20:294–307.

    Article  CAS  Google Scholar 

  5. Petitprez F, de Reynies A, Keung EZ, Chen TWW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577:556–60.

    Article  CAS  Google Scholar 

  6. Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022;55:527–541 e525.

    Article  CAS  Google Scholar 

  7. Mazor RD, Nathan N, Gilboa A, Stoler-Barak L, Moss L, Solomonov I, et al. Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell. 2022;185:1208–1222 e1221.

    Article  CAS  Google Scholar 

  8. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Disco. 2019;18:197–218.

    Article  CAS  Google Scholar 

  9. Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med. 2014;189:832–44.

    Article  CAS  Google Scholar 

  10. Kroeger DR, Milne K, Nelson BH. Tumor-Infiltrating Plasma Cells Are Associated with Tertiary Lymphoid Structures, Cytolytic T-Cell Responses, and Superior Prognosis in Ovarian Cancer. Clin Cancer Res. 2016;22:3005–15.

    Article  CAS  Google Scholar 

  11. Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H. Autoreactivity in human IgG+ memory B cells. Immunity. 2007;26:205–13.

    Article  CAS  Google Scholar 

  12. Atif SM, Gibbings SL, Redente EF, Camp FA, Torres RM, Kedl RM, et al. Immune surveillance by natural IgM is required for early neoantigen recognition and initiation of adaptive immunity. Am J Respir Cell Mol Biol. 2018;59:580–91.

    Article  CAS  Google Scholar 

  13. Rawat, K, Tewari, A, Morrisson, MJ, Wager, TD & Jakubzick, CV. Redefining innate natural antibodies as important contributors to anti-tumor immunity. Elife. 10:e69713 (2021).

    Article  CAS  Google Scholar 

  14. Rawat K, Soucy SM, Kolling FW, Diaz KM, King WT, Tewari A, et al. Natural antibodies alert the adaptive immune system of the presence of transformed cells in early tumorigenesis. J Immunol. 2022;209:1252–9.

    Article  CAS  Google Scholar 

  15. Hu W, Wang G, Wang Y, Riese MJ, You M. Uncoupling therapeutic efficacy from immune-related adverse events in immune checkpoint blockade. iScience. 2020;23:101580.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM, France).

Author information

Authors and Affiliations

  1. Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université Paris Cité, Paris, France

    Robin V. Lacombe, Sophie Sibéril & Jordan D. Dimitrov

Authors
  1. Robin V. Lacombe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sophie Sibéril
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jordan D. Dimitrov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jordan D. Dimitrov.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lacombe, R.V., Sibéril, S. & Dimitrov, J.D. Immature and mature antibodies as defenders against cancer. Cell Mol Immunol 20, 3–5 (2023). https://doi.org/10.1038/s41423-022-00951-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00951-5

Search

Advanced search

Quick links