Summary of clinical trials up to date, investigating the levels, prognostic value, and/or cellular interactions of Th17 cells and/or IL-17 cytokine in CLL
| Location . | No. . | Th17/IL-17 vs HD . | Th17/IL-17 correlation with: . | Key findings . | Reference (y) . | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Disease stage . | Survival . | CD38 . | ZAP-70 . | 11q/17p deletion . | Unmutated IGHV . | |||||
| Germany | 3 | — | — | — | — | — | — | — | Lenalidomide increases Th17 cell percenatge in patients with CLLand reduces Tregs | 165 (2010) |
| USA | 84 | Higher | — | ↑ | ↓ | — | — | ↑ | IL-17 belongs to a cytokine cluster in patients with CLL correlating with longer survival and TTFT | 97 (2011) |
| USA | 66 | Higher | ↓ | ↑ | ↓ | — | ↓ | ↓ | IL-17A+ cells of myeloid lineage present in the proliferation centers of spleens of patients with CLL | 100 (2012) |
| China | 72 | — | — | — | — | — | — | — | Tfh-Th17 (CXCR5+ CCR6+) is significantly elevated in CLL PBMCs, correlating with Binet stage C and mutated IGHV | 33 (2013) |
| Poland | 294 | Higher | ↓ | — | ↓ | ↓ | ↓ | — | Higher Th17 cell and IL-17A levels in patients with CLL are significantly correlated with better therapeutic outcomes and prognostic factors Th17 cell percentage in patients with CLL directly correlates with iNKT cells and inversely with Tregs | 73 (2013) |
| Iran | 40 | — | ↓ | — | NS | NS | — | ↓ | Frequency of Th17 and Tc17 cells is significantly low in patients with progressive CLL and associates with increased CD39+ Tregs | 74 (2013) |
| China | 50 | Higher | — | — | — | — | — | — | Progressive decline in Th17 cell percentage in patients with CLL during 1-year chlorambucil treatment | 99 (2014) |
| India | 40 | Higher | ↑ | — | NS | — | — | — | Th17 cell percentage, not Tregs, is remarkably higher in peripheral blood of patients with CLL who have AIC | 101 (2015) |
| USA | 74 | — | — | — | — | — | — | — | CLL CD4+ T cells have more capacity to differentiate into IL-17F–expressing Th17 cells in vitro Autologous CLL cells are significantly responsible for increasing IL-17F production by Th17 cells in vitro IL-17F activates NF-κB pathway in CLL CD8+ T cells and B cells but not in HD cells | 132 (2015) |
| China | 50 | Higher | ↓ | — | ↓ | ↓ | ↓ | NS | Treg/Th17 and IL-10/IL-17 ratios decrease along CLL progression and can be used as disease prognostic markers | 95 (2016) |
| Sweden | 23 | — | — | — | — | — | — | — | Peripheral blood Th17 cell (CCR6+ CXCR3−) percentage drops significantly starting wk 16 of lenalidomide/alemtuzumab combination therapy | 166 (2017) |
| Italy | 25 | Higher | — | — | — | — | — | — | CLL Tregs express Tbet, GATA-3, and RORγt indicating phenotypic switch to effector subsets Significant increase in IFN-γ/IL-10 and IL-4/IL-10 double-producing CD4+ T cells in peripheral blood of patients with CLL | 51 (2018) |
| Canada | 50 | Higher | NS | — | NS | — | NS | — | In vitro addition of rhIL-17A increases IL-6 expression in human CLL cells and BMMSCs when cultured either alone or in coculture IL-17 increases the engraftment of human CLL cells into NSG mice in peritoneal cavity, spleen, and BM through IL-6–dependent mechanism | 96 (2018) |
| Iran | 78 | Higher | NS | — | NS | ↓ | — | NS | Significant increase in mRNA expression and plasma IL-22 and IL-17 levels in patients with CLL High plasma IL-22 is positively correlated with CD38 and ZAP-70 expression | 98 (2018) |
| USA | 22 | Higher | — | — | — | — | — | — | Ex vivo treatment of PBMCs from patients with CLL with daratumumab increases proportion of Th17 cells In vivo treatment of PDX mice with daratumumab increases Th17 cell percentage | 110 (2020) |
| USA | 75 | — | — | — | — | — | — | — | PMN-MDSCs are more common than monocytic-MDSCs in blood of patients with CLL and correlate more with poor clinical course PMN-MDSCs are more efficient in vitro in inhibiting autologous T-cell proliferation PMN-MDSCs significantly promote in vitro IL-17F production by naïve CD4+ T cells from patients with CLL | 146 (2021) |
| China | 40 | NS | — | — | — | — | — | — | Treg/Th17 and IL-10/IL-17 ratios are significantly higher in patients with CLL Significant increase in Tim-3 expression on CLL Tregs corresponding to disease progression and might be responsible for Treg/Th17 imbalance Galectin-9 serum levels significantly increase in CLL and correlate significantly with IL-10 and Tim-3+ Tregs In vitro blocking of Tim-3 increases CLL cell apoptosis and increases IFN-γ/TNF levels in Tim-3+ Treg/ Th1/CLL cells coculture media | 147 (2021) |
| USA | 30 | — | — | — | — | — | — | — | Activated CLL B cells increase miR-155 expression in T cells leading to increased IL-17F production in vitro which correlates with longer survival and TTFT in patients | 131 (2022) |
| Location . | No. . | Th17/IL-17 vs HD . | Th17/IL-17 correlation with: . | Key findings . | Reference (y) . | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Disease stage . | Survival . | CD38 . | ZAP-70 . | 11q/17p deletion . | Unmutated IGHV . | |||||
| Germany | 3 | — | — | — | — | — | — | — | Lenalidomide increases Th17 cell percenatge in patients with CLLand reduces Tregs | 165 (2010) |
| USA | 84 | Higher | — | ↑ | ↓ | — | — | ↑ | IL-17 belongs to a cytokine cluster in patients with CLL correlating with longer survival and TTFT | 97 (2011) |
| USA | 66 | Higher | ↓ | ↑ | ↓ | — | ↓ | ↓ | IL-17A+ cells of myeloid lineage present in the proliferation centers of spleens of patients with CLL | 100 (2012) |
| China | 72 | — | — | — | — | — | — | — | Tfh-Th17 (CXCR5+ CCR6+) is significantly elevated in CLL PBMCs, correlating with Binet stage C and mutated IGHV | 33 (2013) |
| Poland | 294 | Higher | ↓ | — | ↓ | ↓ | ↓ | — | Higher Th17 cell and IL-17A levels in patients with CLL are significantly correlated with better therapeutic outcomes and prognostic factors Th17 cell percentage in patients with CLL directly correlates with iNKT cells and inversely with Tregs | 73 (2013) |
| Iran | 40 | — | ↓ | — | NS | NS | — | ↓ | Frequency of Th17 and Tc17 cells is significantly low in patients with progressive CLL and associates with increased CD39+ Tregs | 74 (2013) |
| China | 50 | Higher | — | — | — | — | — | — | Progressive decline in Th17 cell percentage in patients with CLL during 1-year chlorambucil treatment | 99 (2014) |
| India | 40 | Higher | ↑ | — | NS | — | — | — | Th17 cell percentage, not Tregs, is remarkably higher in peripheral blood of patients with CLL who have AIC | 101 (2015) |
| USA | 74 | — | — | — | — | — | — | — | CLL CD4+ T cells have more capacity to differentiate into IL-17F–expressing Th17 cells in vitro Autologous CLL cells are significantly responsible for increasing IL-17F production by Th17 cells in vitro IL-17F activates NF-κB pathway in CLL CD8+ T cells and B cells but not in HD cells | 132 (2015) |
| China | 50 | Higher | ↓ | — | ↓ | ↓ | ↓ | NS | Treg/Th17 and IL-10/IL-17 ratios decrease along CLL progression and can be used as disease prognostic markers | 95 (2016) |
| Sweden | 23 | — | — | — | — | — | — | — | Peripheral blood Th17 cell (CCR6+ CXCR3−) percentage drops significantly starting wk 16 of lenalidomide/alemtuzumab combination therapy | 166 (2017) |
| Italy | 25 | Higher | — | — | — | — | — | — | CLL Tregs express Tbet, GATA-3, and RORγt indicating phenotypic switch to effector subsets Significant increase in IFN-γ/IL-10 and IL-4/IL-10 double-producing CD4+ T cells in peripheral blood of patients with CLL | 51 (2018) |
| Canada | 50 | Higher | NS | — | NS | — | NS | — | In vitro addition of rhIL-17A increases IL-6 expression in human CLL cells and BMMSCs when cultured either alone or in coculture IL-17 increases the engraftment of human CLL cells into NSG mice in peritoneal cavity, spleen, and BM through IL-6–dependent mechanism | 96 (2018) |
| Iran | 78 | Higher | NS | — | NS | ↓ | — | NS | Significant increase in mRNA expression and plasma IL-22 and IL-17 levels in patients with CLL High plasma IL-22 is positively correlated with CD38 and ZAP-70 expression | 98 (2018) |
| USA | 22 | Higher | — | — | — | — | — | — | Ex vivo treatment of PBMCs from patients with CLL with daratumumab increases proportion of Th17 cells In vivo treatment of PDX mice with daratumumab increases Th17 cell percentage | 110 (2020) |
| USA | 75 | — | — | — | — | — | — | — | PMN-MDSCs are more common than monocytic-MDSCs in blood of patients with CLL and correlate more with poor clinical course PMN-MDSCs are more efficient in vitro in inhibiting autologous T-cell proliferation PMN-MDSCs significantly promote in vitro IL-17F production by naïve CD4+ T cells from patients with CLL | 146 (2021) |
| China | 40 | NS | — | — | — | — | — | — | Treg/Th17 and IL-10/IL-17 ratios are significantly higher in patients with CLL Significant increase in Tim-3 expression on CLL Tregs corresponding to disease progression and might be responsible for Treg/Th17 imbalance Galectin-9 serum levels significantly increase in CLL and correlate significantly with IL-10 and Tim-3+ Tregs In vitro blocking of Tim-3 increases CLL cell apoptosis and increases IFN-γ/TNF levels in Tim-3+ Treg/ Th1/CLL cells coculture media | 147 (2021) |
| USA | 30 | — | — | — | — | — | — | — | Activated CLL B cells increase miR-155 expression in T cells leading to increased IL-17F production in vitro which correlates with longer survival and TTFT in patients | 131 (2022) |
↓, negative correlation; ↑, positive correlation; —, comparison not studied; HD, healthy donor; No., number of patients; NS, nonsignificant relation found; PDX, patient-derived xenograft.