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.

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…Ample evidence supports a close association between MDSC accumulation and clinical outcome in cancer patients (91). Most solid tumors have expansion of PMN-MDSCs, with some exceptions, including melanoma, multiple myeloma, and prostate cancer.…”

Targeting tumor tolerance: A new hope for pancreatic cancer therapy?

“…MDSC expansion and mobilization is now a hallmark of cancer (Cuenca, et al, 2014;Messmer, et al, 2015). In patients with PC, the leukocyte fraction of circulating MDSCs is elevated and further increases with disease progression (Markowitz, et al, 2015;Porembka, et al, 2012).…”

Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy

“…The use of aberrant myelopoiesis as a biomarker and prognostic indicator for tumor progression has been however hampered by the wide range of markers that have been used to define these cells as mentioned by Messmer et al [44]. Despite this, several studies have convincingly shown the relation between the accumulation of immunosuppressive myeloid cells and tumor progression in a range of tumor types [41-43, 45-47, 50, 100, 101].…”

“…MDSCs isolated from melanoma, glioma, squamous cell carcinoma, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, gastric cancer, colorectal and chronic myeloid leukemia cancer patients have been shown to suppress antigen-specific and CD3-ligation induced T cell proliferation [29, 30, 42, 45, 103]. MDSC expansion has been negatively associated with tumor stage, metastatic burden, response to therapy and progression-free or overall survival [44, 46, 47, 104, 105] .…”

“…T cell immunosuppression by MDSCs creates a huge barrier to the efficacy of immunotherapeutic approaches and therefore it is imperative that strategies that can efficiently block the activity of these cells be developed. As indicated by Messmer et al, certain tumor derived factors such as HMGB1 and S100A8/A9 may act within the tumor microenvironment, while factors like GMCSF, IL-6 and VEGF may act at the systemic level [44]. This is an important consideration for developing therapies that would either be working at the systemic level or locally within the tumor.…”