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Evidence of immune elimination, immuno-editing and immune escape in patients with hematological cancer

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Abstract

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.

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Abbreviations

BCR-ABL1:

Breakpoint cluster region-Abelson murine leukemia virus oncogene homolog

CALR:

Calreticulin

TCM :

Central memory T cell

MPN:

Chronic myeloproliferative neoplasms

TEM :

Effector memory T cell

TEMRA :

Effector memory T cell expressing CD45RA

ET:

Essential thrombocythemia

JAK2:

Janus kinase-2

MART-1:

Melanoma antigen recognized by T-cells

MYD88:

Myeloid differentiation primary response 88

NPM-1:

Nucleophosmine-1

PMF:

Primary myelofibrosis

PV:

Polycythemia vera

TSA:

Tumor specific antigen

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Acknowledgements

We thank Merete Jonassen, laboratory technician, for excellent technical assistance and for teaching Morten Orebo Holmström to perform experiments.

Funding

The writing of this paper and the experiments described herein were partially funded by the Danish Cancer Society (Kræftens Bekæmpelse), Grant numbers R149-A10159-B120 and R90-A6143-14-S2, awarded to Hans Carl Hasselbalch.

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Authors and Affiliations

  1. National Center for Cancer Immune Therapy, Herlev Hospital, Borgmester Ib Juuls Vej 25C, 5. Sal, 2730, Herlev, Denmark

    Morten Orebo Holmström & Mads Hald Andersen

  2. Department of Hematology, Zealand University Hospital, Roskilde, Denmark

    Sabrina Cordua, Vibe Skov, Lasse Kjær & Hans Carl Hasselbalch

  3. Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark

    Niels Pallisgaard

  4. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Christina Ellervik

  5. Department of Production, Research, and Innovation, Region Zealand, Sorø, Denmark

    Christina Ellervik

  6. Department of Laboratory Medicine, Harvard Medical School, Boston Children’s Hospital, Boston, USA

    Christina Ellervik

  7. Institute for Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    Mads Hald Andersen

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  1. Morten Orebo Holmström
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Contributions

MOH: designed the studies, performed the experiments, and wrote the manuscript. SC: designed the studies. VS: designed the studies and performed experiments. LK: designed the studies and performed experiments. NP: designed the studies and performed experiments. CE: designed the studies and performed experiments. HCH: designed the studies and wrote the manuscript. MHA: designed the studies and wrote the manuscript.

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Correspondence to Morten Orebo Holmström.

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Conflict of interest

Morten Orebo Holmström, Mads Hald Andersen, and Hans Carl Hasselbalch have filed a patent regarding CALR exon 9 mutations as targets for cancer immune therapy. The patent has been transferred to Zealand University Hospital, Zealand Region and to Herlev Hospital, Capital Region, Denmark, according to Danish Law concerning inventions created at public research institutions. The authors declare that there are no other conflicts of interest.

Ethical standards

All projects described herein were approved by the local Ethics Committee in Zealand Region, Denmark, with the approval numbers: SJ-456, SJ-585, SJ-114, SJ-113, and SJ-452.

Informed consent

All patients and healthy donors provided both written and oral informed consent on the use of their biological material for research and for publication. The consent was received before the sampling of biological material from the individual.

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Holmström, M.O., Cordua, S., Skov, V. et al. Evidence of immune elimination, immuno-editing and immune escape in patients with hematological cancer. Cancer Immunol Immunother 69, 315–324 (2020). https://doi.org/10.1007/s00262-019-02473-y

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