1. Immunology and Inflammation
Download icon

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
Research Article
  • Cited 0
  • Views 480
  • Annotations
Cite this article as: eLife 2021;10:e69713 doi: 10.7554/eLife.69713

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)

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.

Metrics

  • 480
    Page views
  • 67
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    Kotaro Akaki et al.
    Research Article

    Regnase-1 is an endoribonuclease crucial for controlling inflammation by degrading mRNAs encoding cytokines and inflammatory mediators in mammals. However, it is unclear how Regnase-1-mediated mRNA decay is controlled in interleukin (IL)-1β- or Toll-like receptor (TLR) ligand-stimulated cells. Here, by analyzing the Regnase-1 interactome, we found that IL-1β or TLR stimulus dynamically induced the formation of Regnase-1-β-transducin repeat-containing protein (βTRCP) complex. Importantly, we also uncovered a novel interaction between Regnase-1 and 14-3-3 in both mouse and human cells. In IL-1R/TLR-stimulated cells, the Regnase-1-14-3-3 interaction is mediated by IRAK1 through a previously uncharacterized C-terminal structural domain. Phosphorylation of Regnase-1 at S494 and S513 is critical for Regnase-1-14-3-3 interaction, while a different set of phosphorylation sites of Regnase-1 is known to be required for the recognition by βTRCP and proteasome-mediated degradation. We found that Regnase-1-14-3-3 and Regnase-1-βTRCP interactions are not sequential events. Rather, 14-3-3 protects Regnase-1 from βTRCP-mediated degradation. On the other hand, 14-3-3 abolishes Regnase-1-mediated mRNA decay by inhibiting Regnase-1-mRNA association. In addition, nuclear-cytoplasmic shuttling of Regnase-1 is abrogated by 14-3-3 interaction. Taken together, the results suggest that a novel inflammation-induced interaction of 14-3-3 with Regnase-1 stabilizes inflammatory mRNAs by sequestering Regnase-1 in the cytoplasm to prevent mRNA recognition.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Jason Neidleman et al.
    Research Article

    While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.