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 wild-type (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 three- to fivefold 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 three- to fivefold 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.
Highlights
Tumorigenesis occurs when normal cells accumulate mutations and proliferate out of control
NK cell frequency in the tumors of muMT mice returned to normal WT levels after plasmacytoid dendritic cells (pDCs) depletion (Fig. 3C) These findings suggest that excess pDCs mediate the recruitment of NK cells in muMT mice
These findings indicate that the compensatory mechanism exhibited in the muMT mice derives from the development of pDCs, which are recruited to the tumor microenvironment in significant numbers, secrete high levels of type 1 IFN, and recruit and activate NK cells that promote anti-tumor immunity
Summary
Tumorigenesis occurs when normal cells accumulate mutations and proliferate out of control. In the elimination phase of cancer immunoediting, the identification and destruction of nascent tumors result from the expression of neoantigens by mutant cells, which form a hypoxic cluster and release damage-associated molecular patterns (DAMPs). To induce antigen-specific effector T cell against neoantigens (as with other foreign antigens), dendritic cells (DC) must become licensed through their pattern recognition receptors by either DAMPs or pathogen-associated molecular patterns (PAMPs). This licensing allows for DCs to present neoantigens in an immunogenic fashion to T cells [4]. Newly transformed cells that just escaped intrinsic suppression mechanisms do not express PAMPs but must be eliminated too. How do immune cells become licensed to eliminate newly transformed neoantigen-expressing cells prior to cluster formation and hypoxic conditions?
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