Chromosomal instability can favor macrophage-mediated immune response and induce a broad, vaccination-like anti-tumor IgG response [RNA-Seq]
Chromosomal instability (CIN), a state in which cells undergo mitotic aberrations that generate chromosome copy number variations, generates aneuploidy and is thought to drive cancer evolution. Although associated with poor prognosis and reduced immune response, CIN generates aneuploidy-induced stresses that could be exploited for immunotherapies. Macrophages, particularly, have been understudied in the CIN context. Here, through MPS1 inhibition-induced CIN in poorly immunogenic B16F10 mouse melanoma, we find that CIN- afflicted cancer cells skew macrophages towards an anti-cancer phenotype while also pushing them away from a pro-cancer one. We confirm these findings via RNA-sequencing, protein expression, and short-term tumor studies. These results further translate to in vivo efficacy in suppressing tumor growth: Mice can survive challenges of CIN-afflicted tumors. Long-term survival, however, is dependent on CD47 expression and IgG opsonization. Mice bearing CIN- afflicted tumors with wild-type CD47 levels see prolonged survival compared to their chromosomally stable counterparts, but all succumb. Mice bearing CIN-afflicted CD47 knockout tumors, however, show 28% long-term survival. When CD47 knockout was further paired with IgG opsonization, survival rate increased to 97%. Successful rejection and clearance of CIN- afflicted tumors induced de novo anti-cancer IgG antibodies that were multi-epitope and functionally promoted macrophage-mediated phagocytosis. These de novo IgG antibodies could also suppress in vitro tumoroid and in vivo tumor growth in a CD47 knockout context. These results highlight an unexpected therapeutic benefit from CIN when paired with maximal macrophage anti-cancer activity: an anti-cancer vaccination-like antibody response that can lead to durable cures and further potentiate cell-mediated acquired immunity. Overall design: Mice were subcutaneously injected with B16F10 cells previously treated with MPS1i (reversine) or DMSO vehicle control. Five or ten days after tumor inoculation, mice were euthanized, and tumors were excised and disaggregated for bulk RNA-sequencing.