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For a long time, the transcription factor interferon-regulatory factor 8 (IRF8) has been recognized as a masterpiece for the
development of myeloid cells, and its role as a central regulator of immune responses has now been clarified. IRF8 is also
critical for tumor progression, suggesting its fundamental relevance in multiple aspects of cancer immunosurveillance.
Tumor progression and metastatic inva- malignancy that closely resembles chronic shown to downregulate IRF8 as a mecha-
sion are 2 interconnected phenomena myelogenous leukemia (CML),2 which in nism to avoid apoptosis).7 Accordingly,
characterized by a plethora of relatively humans is associated with the expression gene expression analysis of melanoma
well characterized, sequential events. of the oncogenic fusion protein BCR- developing in Irf8−/− mice evidenced a
The immune system can respond to the ABL.4 IRF8 also plays a role in the biology chemokine/chemokine receptor profile
presence of cancer by actively infiltrating of solid tumors, a setting in which IRF8 compatible with an immunosuppressive
neoplastic lesions and interacting with has been ascribed with oncosuppressive microenvironment that supports tumor
cancer cells and other components of the functions.5 growth and metastasis. Conversely, mela-
tumor microenvironment.1 The profile The mechanisms by which intratu- noma growing in WT animals displayed
of immune cell populations and soluble moral IRF8 expression is regulated in a more immunogenic chemokine expres-
immunomodulatory factors (i.e., cyto- vivo and how this affects the immunoen- sion pattern, supporting the recruitment
kines, chemokines) found within neo- vironment have long remained elusive. of DCs and T cells (Fig. 1).
plastic lesions is sometimes referred to as By using Irf8−/− mice transplanted with On the other hand, the immunologi-
“immunoenvironment” and is thought to highly metastatic B16.F10 melanoma cal defects of Irf8−/− mice were paralleled
critically dictate tumor progression and cells, we recently highlighted a dual role by an early loss of IRF8 expression by
metastatic spread, although the mecha- for IRF8 in the regulation of tumor pro- transplanted B16 melanoma cells. In
nisms underpinning the crosstalk between gression and metastasis. On one hand, the contrast, melanoma lesions developing
immune system and cancer are still poorly lack of IRF8 in the host results in failing in WT mice displayed detectable IRF8
defined. anticancer immunosurveillance, allow- expression, although the levels progres-
Interferon-regulatory factor 8 (IRF8) ing B16 melanoma cells to rapidly grow sively declined along with tumor pro-
shares with all the other members of the and form lung metastases.6 These find- gression. These results suggest that the
IRF protein family the ability to regu- ings could be attributed to the immuno- immunoenvironment is capable of shap-
late type I and II interferon-dependent logical defects displayed by Irf8−/− mice. ing the phenotype of cancer cells in terms
signaling pathways. IRF8 specifically In fact, the analysis of melanoma lesions of gene expression, notably concerning
directs the developmental program of the developing in Irf8−/− hosts revealed pro- the expression of oncosuppressive factors
myeloid cell lineage. Mice lacking the found immunoenvironmental alterations such as IRF8. Co-culture experiments in
murine counterpart of IRF8 are devoid as compared with similar tumors grow- transwell chambers using splenocytes (as a
of plasmacytoid dendritic cells (pDCs) ing in wild-type (WT) mice. Indeed, representative population of bulk immune
and display a selective decrease in the whereas the latter were highly infiltrated cells) and melanoma cells revealed that
number and functionality of CD8α+ DCs by conventional DCs, pDCs, CD4 +, and the expression levels of IRF8 in the lat-
and macrophages along with abnormally CD8 + T lymphocytes, the former were ter can be directly modulated by soluble
elevated frequencies of granulocytes.2,3 rich of immunosuppressive cells popula- factors released by immune cells. Hence,
Of note, Irf8−/− mice are characterized by tions, in particular myeloid-derived sup- while the immunosuppressive microen-
an unusual recurrence of a hematologic pressor cells (which have recently been vironment provided by Irf8−/− mice was
unable to sustain intratumoral IRF8 also be involved in this process. IL-27 is developing in untreated Irf8−/− mice was
expression, the immunoenvironment of an attractive candidate for the develop- highly methylated, the administration of
WT hosts released the soluble mediators ment of anticancer immunotherapeutic decitabine resulted in its specific demeth-
that are required to this aim. Additional interventions, as it mediates antineoplastic ylation, restoring intratumoral IRF8
co-culture experiments performed in a effects against melanoma cells through a expression. These findings confirm the
microfluidic environment (using nano- mechanism that involves the upregulation epigenetic control of Irf8 gene and dem-
fabricated silicon-based devices) con- of IRF1 and IRF8.9 onstrate a close correlation between intra-
firmed the existence of an active crosstalk The administration of the demeth- tumoral IRF8 expression levels and the
between immune cells and malignant ylating agent 5-aza-2'-deoxycytidine immune contexture of melanoma (Fig. 1).
cells modulated by IRF8.8 Thus, IRF8 (decitabine) to melanoma-bearing Irf8−/− Globally, the results of our studies
is capable to selectively induce and sus- mice induced a transient reversion of the identify IRF8 as a crucial modulator of
tain the production of soluble factors that cancer immunoenvironment toward a melanoma progression operating at the
play a pivotal role in the balance between state characterized by DC and T-cell infil- interface between malignant cells and
immunosurveillance and immune escape. tration as well as by a specific chemokine/ the immune infiltrate. We propose that
Interleukin (IL)-27 and IL-6 were identi- chemokine receptor pattern that medi- immune effector cells actively infiltrat-
fied as central factors that modulate IRF8 ated antineoplastic effects. Of note, while ing neoplastic lesions sustain the expres-
expression, although other mediators may the Irf8 promoter in melanoma lesions sion of IRF8 by melanoma cells, and, in