Naive Tumour‐Specific CD4⁺ T Cells were Efficiently Primed in Acute Lymphoblastic Leukaemia

Abstract

1 Authors contributed equally to this work. AbstractThe recognition and neutralization of tumour cells is one of the big challenges in immunity. The immune system has to recognize syngeneic tumour cells and has to be primed and respond in an adequate manner. Priming of a leukaemiaspecific immune response is a crucial step in tumour immunology that can mislead to tumour tolerance either by T cell ignorance, deletion or Treg induction. To resemble the situation of acute lymphoblastic leukaemia (ALL) in patients, we used the murine BALB/c model with syngeneic BM185 tumour cells. We established a tumour cell line that expresses the neo-antigen ovalbumin (BM185-OVA/GFP) to allow the application of T cell receptor transgenic, antigen-specific CD4 + T cells. Here, we demonstrate that effective anti-ALL immunity can be established by in vivo priming of CD4 + T cells that is sufficient to differentiate into effector cells. Yet they failed to control tumour alone, but initiated a Th1 response. An efficient tumour clearance was dependent on both antigen-specific CD4 + T cells and CD8 + effector T cells from the endogenous repertoire. The tolerogeneic milieu was characterized by increased Tregs numbers and elevated IL-10 level. Tregs hamper effective antitumour immune response, but their depletion did not result in reduced tumour growth. In contrast, neutralization of IL-10 improved median mouse survival. Future therapies should focus on establishing a strong CD4+ T cells response, either by adjuvant or by adoptive transfer.

Effect of systemic injection of heterogenous and homogenous opioids on peripheral cellular immune response in rats with bone cancer pain: A comparative study

“…However, a number of studies have indicated that CD4 + T cells contribute to the eradication of tumors even in the absence of CD8 + T cells ( 41 , 42 ). Cytotoxic CD4 + T cells have been shown to be capable of directly eliminating tumor cells that are MHC class II positive, in addition to indirectly killing tumor cells that lack MHC class II expression ( 43 , 44 ). In the present study, it was found that the systemic injection of rat-derived β-EP, a homogenous opioid peptide, increased CD3 + , CD4 + and CD8 + T cell subtype expression in a rat model of bone cancer pain, while the systemic injection of morphine, a heterogenous opioid compound, reduced their expression.…”

Aberrant EPHB4 gene methylation and childhood acute lymphoblastic leukemia

“…Previous studies have reported that the interaction between EPHB4 and ephrin-B2 is involved in the inhibition of T-cell proliferation by activating the Src, phosphoinositide 3-kinase (PI3K), Abelson murine leukemia (Abl) and N-terminal kinase signaling pathways ( 19 ). It has also been suggested that T cells are important in mediating antitumor immune responses; therefore, insufficient priming of CD4+ T cells may result in impaired specific anti-leukemia immunity and subsequently enhance the invasive ability of leukemic cells ( 20 , 21 ). The role of EPHB4 in the modulation of T-cell physiology implies that EPHB4 gene methylation may be associated with ALL pathogenesis ( 22 ).…”