Abstract / Summary
Intact antigen presentation in cancer cells is a key prerequisite for endogenous anticancer T cell responses and a starting point for immunotherapy. Calreticulin was postulated as a chaperone and integral part of the peptide-loading complex of MHC-I. Oncogenic mutations of calreticulin allow surface expression in complex with the thrombopoietin receptor, leading to ligand-independent activation, cell proliferation, and myeloproliferative neoplasms. We hypothesized that mutated calreticulin could also corrupt the function of MHC-I, as previous reports revealed decreased surface expression, peptide-loading defects and retention of MHC-I in the Golgi apparatus. We employed reporter cell models that utilized the T cell response towards target murine and human primary cells and cell lines carrying calreticulin mutations as a functional readout. We also harnessed T cell responses upon a viral infection In Vivo. We found no evidence for immunosuppression in mutant calreticulin-expressing or calreticulin-deficient cells. Our study implies an overestimation of the significance of calreticulin for MHC-I functionality and provides an impulse for reevaluation. Furthermore, we show that calreticulin deficiency affects only a few proteins, including myeloperoxidase and other proteins involved in antibacterial immune mechanisms. In conclusion, mutant calreticulins do not interfere with antigen presentation in MPN, making MHC-I-dependent immunotherapies a viable venue for treatment.