Complement C3d enables cell- mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells

• 成果类型: Article
• 署名作者: Platt, Jeffrey L.; Zhao, Chong; Chicca, Jeffrey; Pianko, Matthew J.; Han, Joshua; The, Stephanie; Rao, Arvind; Keller, Evan T.; Barbosa, Mayara Garcia de Mattos; Naing, Lwar; Pasieka-Axenov, Tracy; Axenov, Lev; Schaefer, Simon; Farkash, Evan; Cascalho, Marilia
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Erlangen Nuremberg; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14352
• DOI: 10.1073/pnas.2405824121
• 发表日期: 2024-12-24
• 关键词: multiple-myeloma; mouse model; maturation; generation; Mutation; therapy; innate

摘要

Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell- mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC- I presentation, and increase MHC- I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell-mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.