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Abstract
Early recognition of neoantigen-expressing cells is complex, involving multiple immune cell types. In this study, in vivo, we examined how antigen-presenting cell subtypes coordinate and induce an immunological response against neoantigen-expressing cells, particularly in the absence of a pathogen-associated molecular pattern, which is normally required to license antigen-presenting cells to present foreign or self-antigens as immunogens. Using two reductionist models of neoantigen-expressing cells and two cancer models, we demonstrated that natural IgM is essential for the recognition and initiation of adaptive immunity against neoantigen-expressing cells. Natural IgM antibodies form a cellular immune complex with the neoantigen-expressing cells. This immune complex licenses surveying monocytes to present neoantigens as immunogens to CD41 T cells. CD41 T helper cells, in turn, use CD40L to license cross-presenting CD401 Batf3+ dendritic cells to elicit a cytotoxic T cell response against neoantigen-expressing cells. Any break along this immunological chain reaction results in the escape of neoantigen-expressing cells. This study demonstrates the surprising, essential role of natural IgM as the initiator of a sequential signaling cascade involving multiple immune cell subtypes. This sequence is required to coordinate an adaptive immune response against neoantigenexpressing cells.
Keywords: Ly6C+ monocytes; XCR11 Batf3+ dendritic cells; neoantigens; cancer; natural IgM;
The immune system recognizes and attacks cancerous cells that express neoantigens, or cell surface markers associated with cellular pathology and aberrant growth (1, 2). Many forms of cancer are thus recognized and destroyed by the intact immune system. This process is also known to involve adaptive immune pathways that result in the differentiation of naive T cells into effector T cells. Such T cell differentiation nearly universally implicates pathogen-associated molecular patterns (PAMPs) or non-PAMP adjuvants (such as Alum)-but in the case of tumor cells, early neoantigen recognition and elimination occurs in the absence of PAMPs. Further understanding how the immune system recognizes neoantigen and orchestrates a T cell-mediated adaptive immune response against neoantigen-expressing cells in the absence of PAMPs could tell us how cancers are suppressed by the healthy immune system, and provide new key targets for diagnosis and intervention.
Studies focusing on extrinsic tumor suppressor mechanisms have paid much attention to the roles played by dangerassociated molecular patterns, dendritic cells (DCs), natural killer (NK) cells, and T cells during the recognition and clearance of...