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

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.

Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis

“…Both adoptively transferred cells, male cells or 129Sv female cells, express normal MHC class I levels and have no tumor-inducing damage signals, and yet an immune response is mounted in WT, but not NAb-deficient, mice. We also found the same to be true regardless of the tumor model we examined, either cell line or chemical induction (18,19). Impending questions remain.…”

“…However, until recently, their fundamental role in preventing tumor formation and recognition of precancerous cells has been overlooked. This is mainly due to the use of a popular B celldeficient mouse, the muMT mouse, which has an abnormal compensatory antitumor immune mechanism (18).…”

“…Recently, we demonstrated that NAbs recognize and bind neoantigens (i.e., new, altered self-antigens) that are not necessarily damaged or senescent (2,18,19). We were initially led to investigate the role of NAbs by observations in unconventional, non cancer-related immune neoantigen models, including syngeneic male cells adoptively transferred into female mice.…”

“…C57BL/6 mice lacking NAbs did not reject 129Sv female cells in circulation. In this setting, the immune response against 129Sv cells in C57BL/6 WT mice is due to the detection of allelic variations outside of the MHC locus by NAbs (18,19). Both adoptively transferred cells, male cells or 129Sv female cells, express normal MHC class I levels and have no tumor-inducing damage signals, and yet an immune response is mounted in WT, but not NAb-deficient, mice.…”

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance

“…Production of type I interferon is carried out by pDCs that mainly do not express the myeloid antigens CD11c, CD33, CD11b, or CD13, in contrast to myeloid cDCs [ 35 ]. Nevertheless, several studies show CD11c expression on pDCs [ 36 , 37 ]. The GMDP markers CD123 (IL-3R) and CD45RA, which are down-regulated when DC progenitors develop into myeloid cDC, are still expressed by them [ 38 ].…”