Dendritic cells initiate adaptive immune responses, leading either to control
cancer by effector T cells or to exacerbate
cancer by regulatory T cells that inhibit IFN-γ-mediated Th1-type response. Dendritic cells can also induce Th17-type immunity, mediated by
IL-17A. However, the controversial role of this
cytokine in
cancer requires further investigations. We generated dendritic cells from peripheral blood monocytes to investigate lifespan, phenotype and chemoresistance of dendritic cells, treated with
IL-17A with or without IFN-γ. Studying the expression of Bcl-2 family members, we demonstrated that dendritic cells constitutively express one pro-survival Bcl-2 member: MCL1. Immature dendritic cells were CD40(low)HLADR(low) CD1a(+) MCL1(+), did not express CD14, CD68 or BCL2A1, and displayed a short 2-day lifespan. IL-17A-treated DC exhibited a semi-mature (CD40(high) HLADR(low)) pre-M2 (CCL22(+) CD206(+) CD163(+) IL1RN(+) IL-10(-) CXCL10(-)
IL-12(-)) mixed (CD1a(+) CD14+ CD68(+)) macrophage-dendritic cell phenotype. They efficiently exerted
mannose receptor-mediated endocytosis and did not produce
superoxide anions, in the absence of TLR engagement. Interestingly,
IL-17A promoted a long-term survival of dendritic cells, beyond 12 days, that correlated to BCL2A1 induction, a pro-survival Bcl-2 family member. BCL2A1 transcription was activated by NF-κB, downstream of
IL-17A transduction. Thus, immature dendritic cells only express MCL1, whereas IL-17A-treated dendritic cells concomitantly expressed two pro-survival Bcl-2 family members: MCL1 and BCL2A1. These latter developed chemoresistance to 11 of the 17
chemotherapy agents tested. However, high doses of either
vinblastine or
cytarabine decreased MCL1 expression and induced dendritic cell death. When
IL-17A is produced in vivo, administration of anti-IL-17A
biotherapy may impair dendritic cell survival by targeting BCL2A1 expression. Consequently, depending on the effector or regulatory role of dendritic cells, blocking
IL-17A, may be either dangerous or beneficial for
cancer outcomes, thus contributing to the apparent controversy around the role of
IL-17A in
cancer.