Tumor-Derived G-CSF Facilitates Neoplastic Growth through a Granulocytic Myeloid-Derived Suppressor Cell-Dependent Mechanism

Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy

Tumor-derived G-CSF promotes granulocytic MDSC development in vivo (66.34)

Abstract Myeloid-derived suppressor cells (MDSC) comprise a heterogeneous population of myeloid cells with the capacity to suppress tumor immunity. Consequently, these cells represent a significant impediment to effective cancer immunotherapy. While the mechanisms by which these cells mediate immunosuppression is well-established, details on how they develop remain poorly understood. Broadly speaking, it is known that tumor-derived factors play significant roles in diverse aspects of MDSC biology. Given that MDSC accumulation is a result of altered myelopoiesis and that a major subset is granulocytic, we tested the hypothesis that tumor-derived granulocyte-colony stimulating factor (G-CSF) promotes MDSC development. Using both implantable and autochthonous mouse mammary tumor models, we observed abundant amounts of G-CSF in vivo, which correlated with a massive accumulation of granulocytic MDSC. To determine a causal role of G-CSF in MDSC generation, we established both gain- and loss-of-function approaches. First, administration of recombinant G-CSF alone elicited immunosuppressive granulocytic MDSC. Secondly, over-expression of G-CSF in G-CSF-negative tumors led to granulocytic MDSC accumulation. Lastly, inhibiting G-CSF culminated in a significant reduction of granulocytic MDSC. Collectively, our studies demonstrate the importance of tumor-derived G-CSF in MDSC development, thus providing new insights into the identity of putative targets for therapeutic applications.</jats:p

IRF-8 levels constrain aberrant myelopoiesis and improve immune control in the metastatic tumor microenvironment (TUM4P.901)

Abstract Abnormal myelopoiesis is common in patients with diverse malignancies, including breast cancer. The myeloid compartment is essential for the induction of host immunity, thus alterations in myelopoiesis may help explain the failure to control neoplastic disease. Therefore, understanding the molecular basis of myeloid dysfunction may improve the efficacy of cancer immunotherapies. Given that interferon regulatory factor-8 (IRF-8) is crucial for myeloid differentiation, we hypothesized that changes in this master regulator underlie a novel mechanism for the altered myelopoiesis and myeloproliferative phenotypes observed in cancer, such as the accumulation of myeloid-derived suppressor cells (MDSC). We recently showed that tumors downregulate IRF-8 expression in myeloid progenitors in a cytokine-driven STAT3 or STAT5-dependent manner, resulting in MDSC generation. This suggested that IRF-8 expression functions as a ‘rheostat’ which directs the fate of the tumor-induced myeloid response. To test this, we examined the impact of modulating IRF-8 levels in two mouse mammary tumor models of lung metastasis using a newly designed genetic gain-of-function approach. In both models, we observed a significant reduction in lung metastases and the frequency of MDSC in IRF-8 transgenic mice compared to wild-type controls. Altogether, our results reveal an unrecognized role for IRF-8 in the host response against metastasis, which may lead to new therapeutic targets in cancer immunotherapy.</jats:p

Emergence of the CD226 Axis in Cancer Immunotherapy

In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of manipulation in cancer. Central to this axis, CD226, TIGIT, and CD96 represent ligand (CD155)-competitive co-stimulatory/inhibitory receptors, analogous to the CTLA-4/B7/CD28 tripartite. The identification of PVRIG (CD112R) and CD112 has introduced complexity and enabled additional nodes of therapeutic intervention. By virtue of the clinical progression of TIGIT antagonists and emergence of novel CD96- and PVRIG-based approaches, our overall understanding of the ‘CD226 axis’ in cancer immunotherapy is starting to take shape. However, several questions remain regarding the unique characteristics of, and mechanistic interplay between, each receptor-ligand pair. This review provides an overview of the CD226 axis in the context of cancer, with a focus on the status of immunotherapeutic strategies (TIGIT, CD96, and PVRIG) and their underlying biology (i.e.,cis/transinteractions). We also integrate our emerging knowledge of the immune populations involved, key considerations for Fc gamma (γ) receptor biology in therapeutic activity, and a snapshot of the rapidly evolving clinical landscape.</jats:p