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