TY - JOUR
T1 - Evidence of immune elimination, immuno-editing and immune escape in patients with hematological cancer
AU - Holmström, Morten Orebo
AU - Cordua, Sabrina
AU - Skov, Vibe
AU - Kjær, Lasse
AU - Pallisgaard, Niels
AU - Ellervik, Christina
AU - Hasselbalch, Hans Carl
AU - Andersen, Mads Hald
PY - 2020/2
Y1 - 2020/2
N2 - There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.
AB - There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.
KW - CALR
KW - CITIM 2019
KW - Immuno-editing
KW - Myeloproliferative neoplasms
KW - Neo-antigen
KW - T cell memory
KW - Hematologic Neoplasms/etiology
KW - Tumor Escape/genetics
KW - Antigens, Neoplasm/immunology
KW - Disease Susceptibility
KW - Epitopes/immunology
KW - Humans
KW - Immunomodulation/genetics
KW - Biomarkers, Tumor
KW - Animals
KW - Cell Transformation, Neoplastic
KW - Mutation
KW - Calreticulin/genetics
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85077561806&partnerID=8YFLogxK
U2 - 10.1007/s00262-019-02473-y
DO - 10.1007/s00262-019-02473-y
M3 - Review
C2 - 31915854
SN - 0340-7004
VL - 69
SP - 315
EP - 324
JO - Cancer immunology, immunotherapy
JF - Cancer immunology, immunotherapy
IS - 2
ER -