Unlike JAK2 and MPL mutations, CALR mutations are frameshift mutations. The mutated CALR protein (mut-CALR) mediates transformation by activating JAK–STAT signaling through its binding to MPL ( 13, 14). Sixty-seven percent of patients with ET and 88% of patients with MF, who lack JAK2 and MPL mutations, carry mutations in the exon 9 of CALR gene ( 11, 12). The initiation and progression of MPN are associated with recurrent somatic driver mutations in Janus kinase 2 ( JAK2), the thrombopoietin receptor gene MPL and calreticulin ( CALR). However, due to intertumoral heterogeneity of mutations, neoantigen-based immunotherapies for the most part remain personalized and limited to individual patients ( 9, 10).īCR–ABL1-negative myeloproliferative neoplasms (MPN), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF), are chronic hematologic malignancies that are characterized by hyperproliferation of blood cells. Neoantigen-specific T cells are not subject to immune tolerance, and hence they have the potential to exhibit strong effector responses specifically against malignant cells. The clinical efficacy of these immunotherapies is correlated in part with mutation load and is likely based on restoring T-cell recognition of neoantigens, non-self antigens that arise from somatic mutations in tumors, in the context of MHC molecules ( 3, 5–8). Blockade of PD-1 and CTLA4 signaling, either alone or in combination, has been reported to reinvigorate tumor antigen-specific T cells, thereby ameliorating antitumor activity ( 3, 4). Inhibition of immune checkpoint receptors, such as PD-1 and CTLA4, in particular, have proved successful in the treatment of several different tumor types, and their combination with other modalities is also gaining approval.

Immune-based therapies have revolutionized the treatment of cancer, resulting in unprecedented response rates and even complete remission ( 1, 2).

Collectively, these results establish mut-CALR as a shared, MPN-specific neoantigen and inform the design of novel immunotherapies targeting mut-CALR. Moreover, mut-CALR elicits antigen-specific responses from both CD4 + and CD8 + T cells, confirming its broad applicability as an immunogen. Significantly, blockade of PD-1 and CLTA4 ex vivo by mAbs and of PD-1 in vivo by pembrolizumab administration restores mut-CALR–specific T-cell immunity in some patients with CALR + MPN. Here, we demonstrate that although a subset of patients with CALR + MPN develop specific T-cell responses against the mut-CALR C-terminus, PD-1 or CTLA4 expression abrogates the full complement of responses. All patients carrying these mutations ( CALR + MPN) share an identical sequence in the C-terminus of the mutated CALR protein (mut-CALR), with the potential for utility as a shared neoantigen. Somatic frameshift mutations in the calreticulin ( CALR) gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN).

Matrix absence management mpn