An Impaired Dnam-1/nkp80 Nk-cell Activation and T-cell Exhaustion Profile at Diagnosis Precede Suboptimal Early Molecular Response in Cml
Year: 2026
Type: article
Study design: Observational Study
Abstract: In Chronic Myeloid Leukemia (CML), early risk assessment traditionally relies on clinical scoring systems such as Sokal and ELTS, which do not capture host immune surveillance, a potential determinant of tyrosine kinase inhibitor (TKI) efficacy. Early identification of patients unlikely to achieve optimal molecular response may be particularly relevant when rapid disease control is clinically desirable. While TKIs modulate cytotoxic responses, the utility of baseline NK and T-cell profiles for early risk stratification remains unexplored. We hypothesized that baseline NK- and T-cell profiles could identify patients at risk of early suboptimal response to TKI therapy. We prospectively evaluated peripheral blood samples from 15 CML patients treated with Imatinib in a Brazilian public healthcare setting across four longitudinal timepoints: diagnosis (DX), 6, 9, and 12 months, alongside healthy donors (HD, n = 19). According to ELN response criteria at 12 months (BCR::ABL1 IS ≤ 0.1%), patients were stratified into Optimal (n = 7) and Warning/Non-Optimal (n = 8) response groups. Baseline clinical risk scores (Sokal and ELTS), age, and sex did not differ between groups. Long-term follow-up data have continuously been collected. NK and T-cell subpopulations, functional maturation, activating receptors, and immune checkpoints were assessed by multiparametric flow cytometry. Patients who subsequently developed a warning response displayed a distinct immune signature already detected at diagnosis. As compared to optimal responders and HDs, those with non-optimal response combined a shift toward innate cell immaturity, with reduced cytotoxic (CD56dim) and mature (CD57+) NK cells, with adaptive alterations including reduced CD8+ effector memory and increased CD8+ naïve T cells. Baseline expression of activating and maturation-associated NK markers, including DNAM1+ NK and NKp80+ cells, was significantly reduced in Warning/Non-Optimal responders, with trends toward lower NKG2D and NKp46. During therapy, only optimal responders progressively reconstituted NKp80 expression back to healthy levels by 12 months. Classical NK inhibitory receptors KIR2DL1, NKG2A, and TIGIT did not discriminate response groups across time. Warning/Non-Optimal responders also displayed elevated baseline PD-1+ and CTLA-4+ T cells. While PD-1 progressively normalized during TKI therapy in Optimal responders, it remained persistently elevated in non-optimal responders. Integration of baseline NK-cell maturation/activation (DNAM-1low and NKp80low NK) and T-cell exhaustion (PD1high) generated an immunological profile capable of discriminating patients acquiring early optimal molecular responses from those developing the warning status. Therefore, a DNAM-1high/NKP80high/PD-1low immune signature identified CML patients who achieved early optimal molecular response, whereas NK-cell immaturity and T-cell exhaustion characterized patients at risk of suboptimal response to Imatinib. In summary, preserved NK cell maturation and low T-cell exhaustion favors early BCR::ABL1 clearance. The novelty of this data is that the abnormal cytotoxic immunophenotype before TKI initiation predicts early response. Our findings highlight that the baseline immune profiling may therefore complement the conventional clinical scores and support personalized TKI management, particularly in resource-constrained healthcare settings, where TKIs are not fully available. Supported by CNPq and FAPESP.
Authors: Larissa Sarri BINELLI, Leonardo Carvalho PALMA, Allana Guimarães de CARVALHO, Camila Araújo Bernardino GARCIA, Mariana MEDEIROS, Beatriz Lima ADJAFRE, Leticia Olops MARANI, Rafael Lopes PACCA, Isabela Catarin ARRUDA, Priscila Santos SCHEUCHER, Josiane Lilian Santos SCHIAVINATO, Robert Samuel WELNER, Kátia Borgia Barbosa PAGNANO, Lorena Lôbo de Figueiredo PONTES
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223124048