Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity

Abstract

Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies. Ferroptosis, a form of cell death that is characterized by iron accumulation and lipid peroxidation, has not yet been fully evaluated from this perspective. Here we present an inducible model of ferroptosis, distinguishing three phases in the process—‘initial’ associated with lipid peroxidation, ‘intermediate’ correlated with ATP release and ‘terminal’ recognized by HMGB1 release and loss of plasma membrane integrity—that serves as tool to study immune cell responses to ferroptotic cancer cells. Co-culturing ferroptotic cancer cells with dendritic cells (DC), reveals that ‘initial’ ferroptotic cells decrease maturation of DC, are poorly engulfed, and dampen antigen cross-presentation. DC loaded with ferroptotic, in contrast to necroptotic, cancer cells fail to protect against tumor growth. Adding ferroptotic cancer cells to immunogenic apoptotic cells dramatically reduces their prophylactic vaccination potential. Our study thus shows that ferroptosis negatively impacts antigen presenting cells and hence the adaptive immune response, which might hinder therapeutic applications of ferroptosis induction.

Ferroptosis: a double-edged sword mediating immune tolerance of cancer

“…Nevertheless, Wiernicki et al held a contradictory perspective, asserting that ferroptotic DCs were unable to resist tumor growth compared to necroptosis and apoptosis, and that ferroptotic cancer cells entirely failed to trigger immune protection in spite of releasing DAMP and cytokines. Ferroptosis adversely affected antigen-presenting cells and the adaptive immune response, which might also interfere with cancer immune treatments, hampering ferroptosis-induced therapeutic applications [ 141 ]. Thus, whether ferroptosis is indeed immunogenic still demands additional work to demonstrate experimentally for a better understanding of its role in anti-cancer therapy.…”

Ferroptosis: Reviewing CRC with the Third Eye

“…Iron as well as ferroptotic cells may also have impacts on the tumor microenvironment and, ultimately, on the tumor behavior. 93 In the future, the execution mechanisms and diverse triggers of ferroptosis need to be identified to selectively and more effectively control ferroptosis and translate it into therapies. We also attach importance to the potential connections with other cell death forms and tumor microenvironment, and the complex network may be a key point to fight against cancer.…”

Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer

“…For instance, the interplay between TNBC cells and macrophages modulates ferroptotic cell death, development, and chemoresistance of TNBC (35). Ferroptosis of cancer cells negatively affects antigen-presenting cells and impedes adaptive immune responses, thereby hindering ferroptosis-induced therapeutic application (36). The LASSO approach is a compressed estimate adopted for acquiring a refined model through building a penalty function, which enables to compress several coefficients and set several coefficients to 0 (37).…”