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).
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