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CML stem cells: evasion for better invasion

Franck Emmanuel Nicolini

In this issue of Blood, Tarafdar et al demonstrate the downregulation of major histocompatibility complex (MHC)-II molecules (and their main regulator class II transactivator [CIITA]) in chronic myeloid leukemia (CML) stem cells, allowing them to evade the immune surveillance exerted by the innate immune system that can be reverted or enhanced by JAK2 inhibitors and interferon γ (IFN-γ).1

For more than 2 decades, the immunogenicity of CML cells has been demonstrated and therapeutically successfully exploited in the allogeneic setting,2,3 leading to indefinite complete molecular remissions in many CML patients, especially those in chronic phase. In addition, the presence of host immune effectors directed against CML aberrantly expressed proteins4 or BCR-ABL peptides5 able to induce an effective lysis of malignant cells has been also demonstrated and exploited in the clinical arena in few patients with real, but less success.6 These issues are still currently under investigation.

In this original work, using a microarray approach, Tarafdar et al carefully examined the expression of MHC-II molecules in progenitor cells of CML patients (CD34+38+, CD34+38, CD34+3890+), comparing them with normal bone marrow counterparts. They explored different hypotheses that may explain why these cells evade the host immune surveillance and persist despite life-long tyrosine kinase inhibitor (TKI) treatment. The expression of MHC-II genes and molecules are specifically reduced in CML stem cells, as is the major regulator of these molecules, CIITA. The addition in culture media of IFN-γ increased the expression of MHC-II molecules, but to a lesser degree than it would do for normal counterparts. The exposure of CML stem cells to 3 different TKIs in vitro for 2 to 7 days did not result in substantial modification of the expression of MHC-II and CIITA, suggesting that this phenomenon is BCR-ABL–independent. The decreased expression does not seem to be mediated via epigenetic mechanisms. Because interleukin-4, a natural antagonist of MHC-II and CIITA expression, signals through the JAK/STAT pathway (as do many other cytokines), the authors demonstrate that the incubation of CML stem cells with the JAK1/2-specific inhibitor Ruxolitinib restored the expression levels of CIITA and MHC-II as a result of the inhibition of JAK-downstream mediators. Finally, Tarafdar et al show that IFN-γ and ruxolitinib increase the proliferation of responder CD4+CD69+ allogeneic T cells in mixed lymphocyte reactions, which could be abolished by the addition of antibodies against MHC-II molecules.

The authors thus provide novel information describing an additional BCR-ABL–independent mechanism that might contribute to the resistance of CML stem cells that persist despite TKI therapy by down-regulating MHC-II molecules, which can be reverted in vitro by ruxolitinib and IFN-γ. These data are in line with previous in vitro and in vivo observations on the efficacy of type I interferons (ie, IFN-α) in CML patients with residual disease on TKI, which may work by restoring MHC-I and MHC-II expression in CML stem cells and allow their recognition by the host immune effectors.7 This study also helps explain data from previous or ongoing trials combining TKIs with (pegylated forms of) IFN-α since diagnosis, showing unexpectedly high molecular response rates.8-10 Responses of 4 ongoing clinical trials in different clinical situations in CML, combining TKI and ruxolitinib as discussed in Tarafdar et al, also support these in vitro observations. That the downregulation of MHC-II and CIITA is intrinsic to CML stem cells or related to some cytokine deregulations within the CML niche, or both, requires further exploration.

Footnotes

  • Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

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