Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T-cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms

Abstract

Somatic frameshift mutations in the calreticulin (CALR) gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN). 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. 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. 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. Moreover, mut-CALR elicits antigen-specific responses from both CD4⁺ and CD8⁺ T cells, confirming its broad applicability as an immunogen. Collectively, these results establish mut-CALR as a shared, MPN-specific neoantigen and inform the design of novel immunotherapies targeting mut-CALR. SIGNIFICANCE: Current treatment modalities for MPN are not effective in eliminating malignant cells. Here, we show that mutations in the CALR gene, which drive transformation in MPN, elicit T-cell responses that can be further enhanced by checkpoint blockade, suggesting immunotherapies could be employed to eliminate CALR ⁺ malignant cells in MPN.This article is highlighted in the In This Issue feature, p. 1143.