INNATE LYMPHOID CELLS ARE EXPANDED AND FUNCTIONALLY ALTERED IN CHRONIC LYMPHOCYTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. De Weerdt I. 06/09/16; 132580; E1031
Mrs. Iris De Weerdt
Contributions
Contributions
Abstract
Abstract: E1031
Type: Eposter Presentation
Background
Both innate and adaptive immune cells markedly affect CLL cells, yet recent findings also highlight reciprocal stimulation of immune cells by clonal B cells. Multi-directional signals derived from a triad formed by malignant cells, lymphocytes and innate immune cells could therefore critically contribute to shaping a supportive environment for the malignant clone. Elucidation of the immune disturbances and tumor microenvironment in CLL is essential for improving therapeutic possibilities and treatment of the CLL immunodeficiency. At the crossroad of innate and adaptive immunity, innate lymphoid cells (ILCs) have recently entered the stage as key players in the initial immune response and tumor surveillance. ILCs have lymphoid morphology but lack rearranged antigen receptors. In addition to NK cells, the ILC family consists of 3 non-cytotoxic groups, mirroring T helper subsets. Group 1 ILCs produce IFN-γ, whereas group 2 ILCs secrete IL-5 and IL-13. Group 3 ILCs produce IL-22 and IL-17, and are subdivided based on the expression of the natural cytotoxicity receptor NKp44. The role of ILC in CLL has not yet been clarified.
Aims
The aim of this study is to investigate the frequency and functionality of ILCs in CLL patients.
Methods
ILCs, defined as lineage-CD127+CD161+ lymphocytes, were measured by flow cytometry in 21 untreated CLL patients and 8 age-matched healthy controls (HCs). We studied functionality of ILCs through measuring cytokine production by flow cytometry upon PMA/ionomycin stimulation in CLL patients (n=6) and HCs (n=6). To assess function after cytokine activation, proliferation and cytokine production was measured in ILC subgroups in 4 CLL patients and 3 HCs.
Results
The number of ILCs in the peripheral blood is significantly increased in CLL patients. Moreover, the ILC count correlates with the absolute leukocyte count in CLL patients, suggesting a rise in ILCs with disease progression. The absolute counts of both ILC1s and NKp44- ILC3s are significantly elevated in comparison to HCs. The activation status of ILCs, as measured by CD69 expression, is similar in CLL patients and HCs.Next, we compared the functionality of ILCs from CLL patients and HCs by measuring cytokine production. TNF-α production is significantly reduced in CLL patients, yet IFN-γ production is comparable between CLL patients and HCs. The production of type 2 (IL-13) and type 3 (IL-22) cytokine production by ILCs in CLL patients is similar to that in HCs.Finally, we investigated whether functional differences remained present upon cytokine activation. In parallel with direct cytokine measurements in the total ILC pool, cultured ILC1s from CLL patients produce less TNF-α, while IFN-γ production by cultured ILC1s was not affected. ILC1s from CLL patients tend to expand slower than their healthy equivalents, although the difference was not statistically significant. In contrast with ILC1s, the expansion and production of IL-17A and IL-22 of NKp44- ILC3s was not affected upon cytokine activation.
Conclusion
Taken together, we demonstrate that in patients with CLL, ILC homeostasis is disturbed. ILCs are expanded in CLL patients and their absolute numbers correlate with disease stage. In addition, ILC1 function is impaired which persists upon cytokine activation. These observations are in line with NK cell alterations and may represent a bystander effect, or reflect functional involvement of ILCs in CLL pathobiology. The extent to which ILCs affect disease progression and therapeutic response is yet to be identified.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia
Type: Eposter Presentation
Background
Both innate and adaptive immune cells markedly affect CLL cells, yet recent findings also highlight reciprocal stimulation of immune cells by clonal B cells. Multi-directional signals derived from a triad formed by malignant cells, lymphocytes and innate immune cells could therefore critically contribute to shaping a supportive environment for the malignant clone. Elucidation of the immune disturbances and tumor microenvironment in CLL is essential for improving therapeutic possibilities and treatment of the CLL immunodeficiency. At the crossroad of innate and adaptive immunity, innate lymphoid cells (ILCs) have recently entered the stage as key players in the initial immune response and tumor surveillance. ILCs have lymphoid morphology but lack rearranged antigen receptors. In addition to NK cells, the ILC family consists of 3 non-cytotoxic groups, mirroring T helper subsets. Group 1 ILCs produce IFN-γ, whereas group 2 ILCs secrete IL-5 and IL-13. Group 3 ILCs produce IL-22 and IL-17, and are subdivided based on the expression of the natural cytotoxicity receptor NKp44. The role of ILC in CLL has not yet been clarified.
Aims
The aim of this study is to investigate the frequency and functionality of ILCs in CLL patients.
Methods
ILCs, defined as lineage-CD127+CD161+ lymphocytes, were measured by flow cytometry in 21 untreated CLL patients and 8 age-matched healthy controls (HCs). We studied functionality of ILCs through measuring cytokine production by flow cytometry upon PMA/ionomycin stimulation in CLL patients (n=6) and HCs (n=6). To assess function after cytokine activation, proliferation and cytokine production was measured in ILC subgroups in 4 CLL patients and 3 HCs.
Results
The number of ILCs in the peripheral blood is significantly increased in CLL patients. Moreover, the ILC count correlates with the absolute leukocyte count in CLL patients, suggesting a rise in ILCs with disease progression. The absolute counts of both ILC1s and NKp44- ILC3s are significantly elevated in comparison to HCs. The activation status of ILCs, as measured by CD69 expression, is similar in CLL patients and HCs.Next, we compared the functionality of ILCs from CLL patients and HCs by measuring cytokine production. TNF-α production is significantly reduced in CLL patients, yet IFN-γ production is comparable between CLL patients and HCs. The production of type 2 (IL-13) and type 3 (IL-22) cytokine production by ILCs in CLL patients is similar to that in HCs.Finally, we investigated whether functional differences remained present upon cytokine activation. In parallel with direct cytokine measurements in the total ILC pool, cultured ILC1s from CLL patients produce less TNF-α, while IFN-γ production by cultured ILC1s was not affected. ILC1s from CLL patients tend to expand slower than their healthy equivalents, although the difference was not statistically significant. In contrast with ILC1s, the expansion and production of IL-17A and IL-22 of NKp44- ILC3s was not affected upon cytokine activation.
Conclusion
Taken together, we demonstrate that in patients with CLL, ILC homeostasis is disturbed. ILCs are expanded in CLL patients and their absolute numbers correlate with disease stage. In addition, ILC1 function is impaired which persists upon cytokine activation. These observations are in line with NK cell alterations and may represent a bystander effect, or reflect functional involvement of ILCs in CLL pathobiology. The extent to which ILCs affect disease progression and therapeutic response is yet to be identified.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia
Abstract: E1031
Type: Eposter Presentation
Background
Both innate and adaptive immune cells markedly affect CLL cells, yet recent findings also highlight reciprocal stimulation of immune cells by clonal B cells. Multi-directional signals derived from a triad formed by malignant cells, lymphocytes and innate immune cells could therefore critically contribute to shaping a supportive environment for the malignant clone. Elucidation of the immune disturbances and tumor microenvironment in CLL is essential for improving therapeutic possibilities and treatment of the CLL immunodeficiency. At the crossroad of innate and adaptive immunity, innate lymphoid cells (ILCs) have recently entered the stage as key players in the initial immune response and tumor surveillance. ILCs have lymphoid morphology but lack rearranged antigen receptors. In addition to NK cells, the ILC family consists of 3 non-cytotoxic groups, mirroring T helper subsets. Group 1 ILCs produce IFN-γ, whereas group 2 ILCs secrete IL-5 and IL-13. Group 3 ILCs produce IL-22 and IL-17, and are subdivided based on the expression of the natural cytotoxicity receptor NKp44. The role of ILC in CLL has not yet been clarified.
Aims
The aim of this study is to investigate the frequency and functionality of ILCs in CLL patients.
Methods
ILCs, defined as lineage-CD127+CD161+ lymphocytes, were measured by flow cytometry in 21 untreated CLL patients and 8 age-matched healthy controls (HCs). We studied functionality of ILCs through measuring cytokine production by flow cytometry upon PMA/ionomycin stimulation in CLL patients (n=6) and HCs (n=6). To assess function after cytokine activation, proliferation and cytokine production was measured in ILC subgroups in 4 CLL patients and 3 HCs.
Results
The number of ILCs in the peripheral blood is significantly increased in CLL patients. Moreover, the ILC count correlates with the absolute leukocyte count in CLL patients, suggesting a rise in ILCs with disease progression. The absolute counts of both ILC1s and NKp44- ILC3s are significantly elevated in comparison to HCs. The activation status of ILCs, as measured by CD69 expression, is similar in CLL patients and HCs.Next, we compared the functionality of ILCs from CLL patients and HCs by measuring cytokine production. TNF-α production is significantly reduced in CLL patients, yet IFN-γ production is comparable between CLL patients and HCs. The production of type 2 (IL-13) and type 3 (IL-22) cytokine production by ILCs in CLL patients is similar to that in HCs.Finally, we investigated whether functional differences remained present upon cytokine activation. In parallel with direct cytokine measurements in the total ILC pool, cultured ILC1s from CLL patients produce less TNF-α, while IFN-γ production by cultured ILC1s was not affected. ILC1s from CLL patients tend to expand slower than their healthy equivalents, although the difference was not statistically significant. In contrast with ILC1s, the expansion and production of IL-17A and IL-22 of NKp44- ILC3s was not affected upon cytokine activation.
Conclusion
Taken together, we demonstrate that in patients with CLL, ILC homeostasis is disturbed. ILCs are expanded in CLL patients and their absolute numbers correlate with disease stage. In addition, ILC1 function is impaired which persists upon cytokine activation. These observations are in line with NK cell alterations and may represent a bystander effect, or reflect functional involvement of ILCs in CLL pathobiology. The extent to which ILCs affect disease progression and therapeutic response is yet to be identified.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia
Type: Eposter Presentation
Background
Both innate and adaptive immune cells markedly affect CLL cells, yet recent findings also highlight reciprocal stimulation of immune cells by clonal B cells. Multi-directional signals derived from a triad formed by malignant cells, lymphocytes and innate immune cells could therefore critically contribute to shaping a supportive environment for the malignant clone. Elucidation of the immune disturbances and tumor microenvironment in CLL is essential for improving therapeutic possibilities and treatment of the CLL immunodeficiency. At the crossroad of innate and adaptive immunity, innate lymphoid cells (ILCs) have recently entered the stage as key players in the initial immune response and tumor surveillance. ILCs have lymphoid morphology but lack rearranged antigen receptors. In addition to NK cells, the ILC family consists of 3 non-cytotoxic groups, mirroring T helper subsets. Group 1 ILCs produce IFN-γ, whereas group 2 ILCs secrete IL-5 and IL-13. Group 3 ILCs produce IL-22 and IL-17, and are subdivided based on the expression of the natural cytotoxicity receptor NKp44. The role of ILC in CLL has not yet been clarified.
Aims
The aim of this study is to investigate the frequency and functionality of ILCs in CLL patients.
Methods
ILCs, defined as lineage-CD127+CD161+ lymphocytes, were measured by flow cytometry in 21 untreated CLL patients and 8 age-matched healthy controls (HCs). We studied functionality of ILCs through measuring cytokine production by flow cytometry upon PMA/ionomycin stimulation in CLL patients (n=6) and HCs (n=6). To assess function after cytokine activation, proliferation and cytokine production was measured in ILC subgroups in 4 CLL patients and 3 HCs.
Results
The number of ILCs in the peripheral blood is significantly increased in CLL patients. Moreover, the ILC count correlates with the absolute leukocyte count in CLL patients, suggesting a rise in ILCs with disease progression. The absolute counts of both ILC1s and NKp44- ILC3s are significantly elevated in comparison to HCs. The activation status of ILCs, as measured by CD69 expression, is similar in CLL patients and HCs.Next, we compared the functionality of ILCs from CLL patients and HCs by measuring cytokine production. TNF-α production is significantly reduced in CLL patients, yet IFN-γ production is comparable between CLL patients and HCs. The production of type 2 (IL-13) and type 3 (IL-22) cytokine production by ILCs in CLL patients is similar to that in HCs.Finally, we investigated whether functional differences remained present upon cytokine activation. In parallel with direct cytokine measurements in the total ILC pool, cultured ILC1s from CLL patients produce less TNF-α, while IFN-γ production by cultured ILC1s was not affected. ILC1s from CLL patients tend to expand slower than their healthy equivalents, although the difference was not statistically significant. In contrast with ILC1s, the expansion and production of IL-17A and IL-22 of NKp44- ILC3s was not affected upon cytokine activation.
Conclusion
Taken together, we demonstrate that in patients with CLL, ILC homeostasis is disturbed. ILCs are expanded in CLL patients and their absolute numbers correlate with disease stage. In addition, ILC1 function is impaired which persists upon cytokine activation. These observations are in line with NK cell alterations and may represent a bystander effect, or reflect functional involvement of ILCs in CLL pathobiology. The extent to which ILCs affect disease progression and therapeutic response is yet to be identified.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia
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