CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

Abstract

Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal‐leukemic hematopoietic cell out‐competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T‐cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin‐like‐2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion‐like phenotype and the functional capability of producing IL‐10 and TGF‐β in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl‐2 interaction, and that the potential regulatory role of exhausted‐like NK cells may favor malignant progression at the expense of anti‐tumor responses. Phenotypic and functional identity of this unique suppressor‐like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

“…A recent investigation has suggested that a low NK cell production in bone marrow from patients suffering from ALL may contribute in disease progression. Moreover, an increase in the percentages of NK cells expressing class I restricted T-cell associated molecule (CRTAM) may be also associated with suppressor properties favoring malignant progression [21].…”

Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia

“…The cell-mediated immunity is activated when a specific CTL is stimulated to initiate the lysis of pathogens, infected cells, and tumor cells; thus, this protects the body against infection and tumor growth, spreading, and metastasis ( 31 ). To prevent tumor emergence, the immune system eliminates oncogenic viral infections, induces the inflammatory microenvironment, and destroys malignant cells ( 32 , 33 ). Although tumor cells are self in origin, they differ from their normal counterparts in their biochemical and antigenic characteristics and biological behavior.…”

“…Tumor-specific CD8+ and CD4+ T cells infiltrate the tumor site after the recognition of tumor-specific or tumor-associated antigens through HLA class I and class II molecules, respectively, which facilitate the immune mechanisms in synergy with B cells. Cancer cells that are not eradicated during the elimination phase remain in dormancy or equilibrium ( Figure 1 ) ( 33 , 43 ).…”

“…Based on CD56 and CD16 expression, two principal subpopulations of NK cells were identified: cytotoxic NK cells or cNK (CD56dim CD16+) and regulatory NK cells or NKregs (CD56highCd16-). cNK are abundant in peripheral blood (95% of the NK) and inflammation sites and show a higher cytotoxic capacity than NKregs, which predominate in lymphoid nodes ( 33 ). Natural cytotoxic receptor expression is a relevant mechanism to stimulate responses against tumor cells and has been observed to be downregulated in ALL BM ( 33 ).…”

Interactions between islets and regulatory immune cells in health and type 1 diabetes

“…Dysregulated ILC responses are also linked to a variety of autoimmune, fibrotic and rheumatoid diseases [81], making defining factors that direct ILC tissue-reparative vs proinflammatory programmes a major focus of ILC research. Complicating our understanding of ILCs further, several 'regulatory' populations of ILCs have been described, including regulatory NKlike cells that have cytokine profiles distinct from those of conventional NK cells [82][83][84], ILCregs which produce IL-10 and TGF-β and are defined by DNA-binding protein inhibitor ID3 expression [85], and IL-10-producing ILC2s that secrete IL-10 downstream of retinoic acid or IL-2 [85][86][87]. These regulatory ILC populations can limit autologous or allogeneic immune responses in diverse contexts [20,81,88], yet whether they have applications for type 1 diabetes is a relatively unexplored area of research.…”