Caspase-8 Contributes to Immuno-Hot Microenvironment by Promoting Phagocytosis via an Ecto-Calreticulin-dependent Mechanism

Abstract Background Caspase-8 play as an initiator caspase of cell apoptosis signaling. However, the role of caspase-8 in tunning tumor immune microenvironment remains controversial due to a complicated crosstalk between immuno-tolerogenic apoptotic cell death and immunogenic cell death (ICD) cascades. Methods TCGA and publicly accessible immune checkpoint blockade (ICB)-treated cohort were introduced to investigate the clinical relevance of caspase-8. Tumor-bearing mouse model was used to characterize the change of tumor microenvironment and explore efficacy to ICB treatment in caspase-8 knockout condition. Results We showed that the expression level of Casp8 was associated with an immuno-hot microenvironment across various solid tumor types by exploring TCGA dataset. Casp8 deficiency led to decreased CD8 + T cell infiltration and resistance to αPD-L1 therapy in mouse model. Mechanistically, Casp8 deficiency or pharmacological disruption resulted in impaired ecto-calreticulin (ecto-CRT) transition on tumor cells, which in turn hampered antigen presentation in draining lymph node. Furthermore, radiotherapy restore the sensitivity to αPD-L1 treatment via elevated surface expression of CRT. Conclusions Our data revealed a causative role of Casp8 in modulating immunogenicity of tumor cells and responsiveness to immune checkpoint blockade immunotherapies and proposed that radiotherapy as a salvage approach to overcome Casp8 deficiency-mediated ICB resistance.