Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value

Abstract

The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance.

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

“…However, downregulation of HLA genes was in most of cases not associated with genomic alterations, underpinning the existence of other non-genomic mechanisms as suggested by previous observations 7 , 53 . While it is important to point out that baseline HLA expressions may be determined by the genetic subtype of AML (for instance, NPM1 mutant leukemias were reported by us and others to have relatively low HLA-DR expression) 41 , 54 , 55 , our analysis illustrates the dynamic changes in HLA expression, drastically reduced in most of post-transplant relapses, independently of the molecular disease subgroup.…”

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

“…However, downregulation of HLA genes was in most of cases not associated with genomic alterations, underpinning the existence of other non-genomic mechanisms as suggested by previous observations. 7,52 While it is important to point out that baseline HLA expressions may be determined by the genetic subtype of AML (for instance, NPM1 mutant leukemias were reported by us and others to have relatively low HLA-DR expression), 53,54,41 our analysis illustrates the dynamic changes in HLA expression, drastically reduced in most of post-transplant relapses, independently of the molecular disease subgroup.…”

Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

“…In human cancer tissues, VISTA expression was mostly enriched in tumor-infiltrating myeloid cells and T cells ( 75 , 85 ). In addition to immune cells, VISTA expression was detected in mesothelioma ( 86 ), gastric cancer ( 87 ), and AML ( 83 , 88 , 89 ). VISTA expression has been associated with resistance to immunotherapy and poor patient survival in many cancers, including prostate cancer, lymphoma, bladder cancer, melanoma, breast cancer, and AML ( 88 , 90 – 95 ),…”