CML-511 T-Cell Exhaustion and Immune Checkpoint VISTA Overexpression Are Associated With Suboptimal Response to Tyrosine Kinase Inhibitors (TKIs) in Patients With Chronic Myeloid Leukemia (CML)

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2023-09, Vol.23, p.S346-S346
• Main Authors: Bidikian, Aram, Basu, Sreyashi, He, Zhong, Atluri, Himachandana, Zarka, Jabra, Andreeff, Michael, Sasaki, Koji, Jabbour, Elias, Cortes, Jorge E., Sharma, Padmanee, Issa, Ghayas C.
• Format: Article
• Language: English
• Subjects: chronic myeloid leukemia; immune response; T cells; tyrosine kinase inhibitor; VISTA
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/S2152-2650(23)01150-3

The role of the immune system in eradicating CML has been demonstrated in multiple settings, including successful graft-versus-leukemia effects and the requirement of active T cells for sustained remission before therapy discontinuation. To further understand the immune determinants of TKI response in CML, to help improve the odds of deeper responses and, eventually, treatment-free remission. We custom-designed a cytometry by time of flight (CyTOF) panel (36-plex) to analyze blood and bone marrow samples prospectively collected from 52 CML patients. The panel included markers of leukemia/stem progenitor cells, lineage differentiation, and immune exhaustion/activation. Leukocytes with high levels of cluster of differentiation 45 (CD45hi) were grouped using PhenoGraph clustering, based on marker expression. Twenty patients who achieved molecular response with a 4.5-log reduction (MR4.5) during treatment were compared with a cohort of 32 patients with suboptimal response (failure to meet ≥1 European LeukemiaNet [ELN] response milestone). Differential expression pattern analysis revealed 25 distinct clusters. Compared with patients with deep molecular response, patients with suboptimal response had a higher proportion of exhausted CD3+CD8+ cytotoxic T cells characterized by high EOMES and low Tbet transcription factor expression (median, 8.0% vs 1.9%; P=0.04). In contrast, CD56+ natural killer cells were more prevalent in the optimal response group, particularly an interferon gamma–releasing (CD56hiCD16loTbet+) subpopulation (median, 4.1% vs 2.5%; P=0.04). While macrophages (CD68+) were detected at similar rates in both response groups, the phagocytic subpopulation (CD16–CD14+CD68+human leukocyte antigen [HLA]-DR isotype–lo) was more prevalent in those who achieved optimal response (median, 15.1% vs 13.2%; P=0.02). Patients with suboptimal response had a higher proportion of macrophages expressing the immune regulatory ligand VISTA (V-domain immunoglobulin suppressor of T cell activation) (median, 5.6% vs 1.8%; P=0.004). Like programmed cell death ligand 1 (PD-L1) and other B7 family ligands, VISTA attenuates T-cell response to antigens; VISTA overexpression has been associated with solid-tumor resistance to immune checkpoint inhibitors. There was a higher proportion of mature granulocytes with low expression of VISTA (CD66b+C-X-C motif chemokine receptor 4 [CXCR4]+VISTAlo) in patients with optimal response (median, 20.6% vs 0.6%; P=0.01). T-cell exhaustion an