Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy

Abstract

Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: (1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; (2) examine the potential mechanisms underlying these clinical manifestations; and (3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response. We posit that fundamental alterations in myeloid homeostasis triggered by the neoplastic process represent critical checkpoints that govern therapeutic efficacy, as well as offer novel cellular-based biomarkers for tracking changes in disease status or relapse.

Fig. 1

Myeloid cells bridge pro-tumor and antitumor immune responses. In a mature, activated state myeloid cells can serve as effective antigen-presenting cells (left, red) to stimulate naïve T cells (center, orange) through the provision of antigen on MHC (1) concurrent with co-stimulation via CD80/CD86 (2) as well as production of inflammatory cytokines IL-12 and IFNγ (3). The convergence of these three signals activates the T cell which undergoes clonal expansion and trafficking to the site of pathogenesis (tumor), where T cells are capable of suppressing tumor growth through induction of apoptosis. Alternately, myeloid cells in an immature or aberrant state of activation behave as myeloid-derived suppressor cells (right, blue) and are unable to effectively stimulate naïve T cells (4) due to reduced antigen processing/presentation or down-regulated co-stimulatory molecules. Additionally, these cells produce cytokines such as IL-10 and TGFβ, as well as other molecules such as Arg-1 and IDO, that directly suppress T cell function and inhibit proliferation (5). These factors can also drive the expansion of T regulatory cells, further contributing to effector T cell suppression. Finally, independent of immune-based effects, MDSC have also been shown to directly promote tumor growth through production of MMPs, VEGF and TGFβ (6)

Fig. 2

Tumor induction of aberrant myelopoiesis occurs among progenitor cells within the bone marrow. Myelopoiesis proceeds through stepwise differentiation in the bone marrow (purple shaded cells). At the GMP stage, the transcription factor IRF-8 serves as a key regulator of development, controlling both the quantity and character of the myeloid output, such that high expression of IRF-8 favors the monocytic lineage (red cell) and overall reduced myeloid numbers. Tumors secrete a variety of factors such as G-CSF that act in a systemic way to reduce IRF-8 within progenitor cells, releasing myelopoiesis from IRF-8 control such that the granulocytic lineage (blue cell) undergoes hyperplasia, leading to increased immature suppressive cells to promote tumor growth