Abstract
Simple SummaryIn in vitro co-cultures of CLL cells and nurse-like cells (NLC), protection against apoptosis is only provided by M2-like NLC, and not M1-like NLC. In this study, we propose that fine-tuning of NLC polarization (and therefore survival of leukemic cells) is dictated by a balance between IL-10 and TNF.Tumor-associated macrophages (TAMs) in chronic lymphocytic leukemia (CLL) are also called nurse-like cells (NLC), and confer survival signals through the release of soluble factors and cellular contacts. While in most patient samples the presence of NLC in co-cultures guarantees high viability of leukemic cells in vitro, in some cases this protective effect is absent. These macrophages are characterized by an “M1-like phenotype”. We show here that their reprogramming towards an M2-like phenotype (tumor-supportive) with IL-10 leads to an increase in leukemic cell survival. Inflammatory cytokines, such as TNF, are also able to depolarize M2-type protective NLC (decreasing CLL cell viability), an effect which is countered by IL-10 or blocking antibodies. Interestingly, both IL-10 and TNF are implied in the pathophysiology of CLL and their elevated level is associated with bad prognosis. We propose that the molecular balance between these two cytokines in CLL niches plays an important role in the maintenance of the protective phenotype of NLCs, and therefore in the survival of CLL cells.
Highlights
Nurse-like cells (NLC) are recognized as tumor-associated macrophages (TAMs) found in the lymphoid organs of chronic lymphocytic leukemia (CLL) patients [1]
We further enriched the analysis with several myeloid markers to better distinguish potential differences between NLC from PBMC with low CLL cells in vitro viability and from PBMC with high CLL cells in vitro viability, In comparison to isotypic controls, expression of CD163, CD206, CD169, CD209, and CD14 was higher for NLC from samples with high viability (Figure 1D: green) compared to expression by NLC from samples with low viability (Figure 1D: red)
Even though TNF was shown in some studies as increasing CLL cells viability and correlated with a bad prognosis in patients [22,25], we showed here that it is able to block or depolarize the M2 protective phenotype of NLC leading to a decrease in leukemic viability (Figure 3)
Summary
Nurse-like cells (NLC) are recognized as tumor-associated macrophages (TAMs) found in the lymphoid organs of chronic lymphocytic leukemia (CLL) patients [1]. TAMs, like other macrophages, are highly plastic and readily respond to signals from the microenvironment by fine-tuning their polarization status Their phenotype will depend on the balance between various pro-M1 factors, such as TNF, IFN-γ, or pro-M2 factors including IL-4, IL-13, or IL-10 [20]. NLC were clearly defined to be closer to the M2 end of the spectrum regarding their phenotype and their pro-survival properties [21] (for review) Both TNF and IL-10 are implicated in the pathophysiology of CLL, levels of which have been correlated with an adverse prognosis in vivo [22,23,24]. IL-10 thwarts anti-tumoral immune responses, inhibits pro-inflammatory cytokines like TNF, and increases the level of pro-survival molecules such as ICAM-1 on the surface of CLL cells [26,27,28]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
