Low-Intensity CD66c Expression Orchestrates an Immunosuppressive Niche Promoting Residual Disease in Pediatric ProB Acute Lymphoblastic Leukemia

TL;DR

Low CD66c expression in pediatric leukemia cells helps them hide from the immune system, leading to higher relapse and mortality risks.

Contribution

The study reveals that low-intensity CD66c expression creates an immunosuppressive niche in bone marrow, promoting residual disease in ProB-ALL.

Findings

ProB-ALL blasts with low CD66c expression show a 'molecular stealth' phenotype linked to higher MRD and mortality.

Low CD66c expression leads to bi-directional remodeling of the bone marrow niche, fostering immune evasion.

Patients with low CD66c expression are at higher risk of relapse and misclassification by standard diagnostic methods.

Abstract

What are the main findings?
ProB-ALL blasts with low-intensity CD66c expression exhibit a “molecular stealth” phenotype associated with a significantly higher risk of detectability of Measurable Residual Disease and mortality.Leukemic CD66clow cells orchestrate a bi-directional remodeling of the bone marrow niche.

ProB-ALL blasts with low-intensity CD66c expression exhibit a “molecular stealth” phenotype associated with a significantly higher risk of detectability of Measurable Residual Disease and mortality.

Leukemic CD66clow cells orchestrate a bi-directional remodeling of the bone marrow niche.

What are the implications of the main findings?
Beyond binary (positive/negative) CD66c assessment leading to intensity-based immunophenotypic substratification is essential for identifying hidden chemoresistant reservoirs at diagnosis.The low immunogenicity CD66clow blast population identifies high-risk patients who would otherwise be misclassified by conventional cytometric thresholds.

Beyond binary (positive/negative) CD66c assessment leading to intensity-based immunophenotypic substratification is essential for identifying hidden chemoresistant reservoirs at diagnosis.

The low immunogenicity CD66clow blast population identifies high-risk patients who would otherwise be misclassified by conventional cytometric thresholds.

Background/Objectives: B-cell precursor acute lymphoblastic leukemia (B-ALL), the most common pediatric acute leukemia (AL), is frequently characterized by aberrant antigen expression, which aids diagnosis and prognosis. The myeloid antigen CD66c is notably frequent in B-ALL and has been proposed as a marker of disease aggressiveness and treatment response. Evaluating CD66c in Mexican pediatric patients may provide insights into disease biology. Methods: A cohort of 128 pediatric patients was referred to the Laboratory of Oncoimmunology and Cytomics of Childhood Cancer (OCL) at Instituto Mexicano del Seguro Social (IMSS) for immunophenotyping tests between March 2022 and November 2023. Additionally, control bone marrow (BM) samples were assessed. Aberrant antigen expression in hematopoietic populations and BM microenvironment stroma phenotyping were performed. Results: In total, 84.38% of B-ALL patients exhibited aberrant expression of ≥1 myeloid antigen. Among CD66c-positive patients, 13.79% had detectable measurable residual disease (MRD) during follow-up and 20.69% died. Mesenchymal stromal cells (MSCs) from patients with positive or low CD66c expression displayed inflammatory profiles. ProB leukemias with low CD66c expression were more likely to exhibit detectable MRD, increased mortality, and reduced survival. Conclusions: Low CD66c expression induces molecular stealth that could favor immune evasion and niche persistence, thereby increasing the risk of relapse and therapeutic failure.

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