Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications.

Immune evasion is a hallmark of cancer. While there are multiple different mechanisms that cancer cells employ, myeloid-derived suppressor cells (MDSCs) are one of the key drivers of tumor-mediated immune evasion. MDSCs begin as myeloid cells recruited to the tumor microenvironment, where they are transformed into potent immunosuppressive cells. However, our understanding of the clinical relevance of MDSCs in cancer patients has significantly lagged behind the preclinical literature in part due to the absence of a cognate molecule present in mice, as well as to the considerable heterogeneity of MDSCs. However, if one evaluates the clinical literature through the filter of clinically robust endpoints, such as overall survival, three important phenotypes emerge: promyelocytic, monocytic, and granulocytic. Based on these studies, MDSCs have clear prognostic importance in multiple solid tumors, and emerging data support the utility of circulating MDSCs as a predictive marker for cancer immunotherapy, and even as an early leading marker for predicting clinical response to systemic chemotherapy in patients with advanced solid tumors. More recent preclinical data in immunosuppressed murine models suggest that MDSCs play an important role in tumor progression and the metastatic process that is independent of their immunosuppressive properties. Consequently, targeting MDSCs either in combination with cancer immunotherapy or independently as part of an approach to inhibit the metastatic process appears to be a very clinically promising strategy. We review different approaches to target MDSCs that could potentially be tested in future clinical trials in cancer patients.

The cardioprotective protein apolipoprotein A1 promotes potent anti-tumorigenic effects.

Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b(+) F4/80(+) macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.

Antitumour and immune-adjuvant activities of protein-tyrosine kinase inhibitors.

The immunologic approach to tumour therapy is hampered by the development of direct immune escape mechanisms and the induction of an immunosuppressive tumour microenvironment characterised by the expansion of myeloid-derived suppressor cells (MDSCs) and tumour-specific regulatory T cells (Tregs). The implementation of inhibitors targeting protein tyrosine kinases, which are involved in the process of tumour development and angiogenesis, has produced robust clinical responses. The consequences of these compounds on the functionality of immune effector cells have been investigated. This review summarises recent reports on the direct and indirect effects of protein tyrosine kinase inhibitors (TKIs) on the immune system and discusses the application of immunotherapeutic strategies in combination with these inhibitors to improve the efficacy of immune-based therapies.