Redefining innate natural antibodies as important contributors to anti-tumor immunity

  1. Kavita Rawat
  2. Anita Tewari
  3. Madeline J Morrisson
  4. Tor D Wager
  5. Claudia Jakubzick  Is a corresponding author
  1. Dartmouth College, United States

Abstract

Myeloid, T and NK cells are key players in the elimination phase of cancer immunoediting, also referred to as cancer immunosurveillance. However, the role of B cells and NAbs, which are present prior to the encounter with cognate antigens, has been overlooked. One reason is due to the popular use of a single B cell-deficient mouse model, muMT mice. Cancer models using muMT mice display a similar tumor burden as their WT counterparts. Empirically, we observe what others have previously reported with muMT mice. However, using two other B cell-deficient mouse models (IgHELMD4 and CD19creDTA), we show a 3 to 5-fold increase in tumor burden relative to WT mice. In addition, using an unconventional, non-cancer-related, immune neoantigen model where hypoxic conditions and cell clustering are absent, we provide evidence that B cells and their innate, natural antibodies (NAbs) are critical for the detection and elimination of neoantigen-expressing cells. Finally, we find that muMT mice display anti-tumor immunity because of an unexpected compensatory mechanism consisting of significantly enhanced Type 1 interferon (IFN)-producing plasmacytoid dendritic cells (pDCs), which recruit a substantial number of NK cells to the tumor microenvironment compared to WT mice. Diminishing this compensatory pDC-IFN-NK cell mechanism revealed that muMT mice develop a 3 to 5-fold increase in tumor burden compared to WT mice. In summary, our findings suggest that NAbs are part of an early defense against not only microorganisms and dying cells, but precancerous cells as well.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files has been provided for Figure 4.

Article and author information

Author details

  1. Kavita Rawat

    Dartmouth College, Lebanon, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anita Tewari

    Dartmouth College, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Madeline J Morrisson

    Dartmouth College, Lebanon, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tor D Wager

    Dartmouth College, Hanover, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Claudia Jakubzick

    Dartmouth College, Lebanon, United States
    For correspondence
    claudia.jakubzick@dartmouth.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3731-0198

Funding

National Heart, Lung, and Blood Institute (R01 HL115334)

  • Claudia Jakubzick

National Heart, Lung, and Blood Institute (R01 HL135001)

  • Claudia Jakubzick

National Heart, Lung, and Blood Institute (R35 HL155458)

  • Claudia Jakubzick

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The mice were housed in a specific pathogen-free environment at Dartmouth Hitchcock Medical College, an AAALAC accredited institution, and used in accordance with protocols approved by the Institutional Animal Care and Utilization Committee of Dartmouth College (#00002229a). The institutional welfare assurance number is A3259-01.

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Publication history

  1. Received: April 23, 2021
  2. Accepted: September 29, 2021
  3. Accepted Manuscript published: October 5, 2021 (version 1)
  4. Version of Record published: October 26, 2021 (version 2)
  5. Version of Record updated: October 27, 2021 (version 3)

Copyright

© 2021, Rawat et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kavita Rawat
  2. Anita Tewari
  3. Madeline J Morrisson
  4. Tor D Wager
  5. Claudia Jakubzick
(2021)
Redefining innate natural antibodies as important contributors to anti-tumor immunity
eLife 10:e69713.
https://doi.org/10.7554/eLife.69713

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