Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function – implications for the adoptive immunotherapy of leukaemia

Abstract

SUMMARYEvidence of an immune mediated graft-versus-leukaemia effect has led to the belief that T and NK cell based adoptive immunotherapy can constitute effective treatment for relapsed leukaemias. However, work on solid tumours has shown this strategy may be hampered, by an immune escape mechanism in which tumour secreted immunosuppressive factors compromise T and NK cell function. Indeed, acute myeloid leukaemia (AML) cells secrete immunosuppressive factors that block the synthesis of Th1 type cytokines in T cells. We demonstrate here that this immunosuppression, mediated by both HL60 AML cell line and primary AML blasts, inhibits T and NK cell proliferation but not cytolytic activity. Supernatants from HL60 cell line and primary AML blasts inhibited T cell proliferation to mitogenic and alloantigen stimulation but had no effect on cytolytic function. Similarly, the proliferation of NK cells to IL-2 and IL-15 stimulation was inhibited whilst their cytolytic function, shown by lysis of AML blasts, K562 and Daudi cells remained unaffected. The failure of T and NK cells to proliferate was not due to effector cell apoptosis. Indeed, removal of lymphocytes from the immunosuppressive environment partially restored their capacity to respond to mitogenic stimulation. T cells exposed to immunosuppressive supernatants did not increase expression of mitotic inhibitory proteins that arrest cell division, thereby ruling this out as a mechanism of operation for this immunosuppression. T cell expansion requires antigen stimulation, usually provided in the form of AML blasts, therefore our data suggest that NK cells may be more practical for the immunotherapy of AML.

Natural killer cell immune escape in acute myeloid leukemia

“…Release of immunosuppressive cytokines, impaired NK cell-mediated cytotoxicity and IFN-g secretion Altered CD137-CD137L expression 46 Increased NK cell CD137 (CD137L expression is related to monocytic differentiation) Impaired cytotoxicity and IFN-g secretion Release of immunosuppressive cytokines Increased AML cell CD137L High AML cell CD200 expression 47 Reduced frequency of activated NK cells, dull NCR profile Impaired NK cell-mediated cytotoxicity and IFN-g secretion Secretion of soluble immunosuppressive factors For example, TGF-b 51 and IL-2R 48,50,108 Inhibition of NK cell proliferation 109 and cytotoxicity 49,51 Resistance of AML cells to killing Defects in apoptosis mechanisms, [52][53][54] resistance to TRAIL and Fas-mediated killing by high decoy 58,59 or low receptor expression [55][56][57] Impaired NK cell-mediated cytotoxicity activating and inhibitory signals tipping over towards the former. As mentioned before, signaling is relayed through a variety of NK cell activating and inhibitory receptors following ligation (depicted in Figure 2).…”

Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

“…3,4 The ability of AML blasts to remain protected from the graft-versusleukemia effect has been incompletely studied to date. [5][6][7] In this study, we elucidate the mechanisms by which AML blasts hamper immune responses by demonstrating that secretion of arginase II from AML blasts significantly affects T-cell proliferation and polarizes monocytes toward an immunosuppressive M2-like phenotype. In addition, the increased arginine metabolism inhibits the proliferation of hematopoietic progenitors, contributing to a wider suppressive microenvironment in AML.…”

Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91phox expression and the PARP-1/PAR pathway of apoptosis

“…13 In addition, multiple deficiencies of T-and NK-cell functions, with ensuing relapse risk and poor prognosis, have been observed in patients with AML who did not undergo transplantation. [14][15][16][17][18] In earlier studies, investigators demonstrated that nonmalignant phagocytic cells down-modulate lymphocyte functions by producing and releasing NADPH oxidase-derived reactive oxygen species (ROS). [19][20][21][22][23] These findings have formed the basis for the use of a NADPH oxidase inhibitor in conjunction with IL-2 as a relapsepreventive strategy in patients with AML.…”