Migration of Myeloid-derived Suppressor Cells to Tumor and Tumor-Draining Lymph Node in a Murine Model of Breast Cancer

Myeloid-derived suppressor cells (MDSC) consist of two major subsets, monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC), both of which expand in cancer and suppress the activation of naïve T cells in the tumor-draining lymph node (TDLN) and the function of effector T cells in the tumor microenvironment. Thus, the ability of MDSC to enter the TDLN and the tumor is likely to be critical for suppression of the anti-tumor immune response. L-selectin mediates the homing of circulating naïve lymphocytes to lymph nodes and the migration of conventional myeloid cells, such as neutrophils and monocytes, to sites of inflammation, but its contribution to MDSC migration is unknown. Using the 4T1 murine breast cancer model, we demonstrated that MDSC express L-selectin and integrins necessary for migration to TDLN and inflammatory sites, such as the tumor. We then demonstrated involvement of L-selectin in the migration of PMN-MDSC, but not M-MDSC, to tumors and TDLN. This suggests that M-MDSC may utilize L-selectin-independent mechanisms for migration. After entry into the tumor, MDSC migrated through the tumor parenchyma and associated with MDSC aggregates localized in the immediate vicinity of hypoxic areas. BrdU incorporation experiments showed that approximately 20% of tumor-infiltrating MDSC were undergoing in situ proliferation in the tumor microenvironment. Thus, in addition to MDSC recruitment to tumors, intratumoral proliferation of MDSC may also contribute to MDSC accumulation. Hypoxia-inducible factor (HIF) is an intracellular sensor of hypoxia, which functions to activate the expression of genes necessary for adaptation to hypoxic conditions. There are several HIF isoforms with both overlapping and opposing roles in various processes, including proliferation. Although our preliminary experiments did not confirm a role for HIF in inducing proliferation of tumor-infiltrating MDSC, the specific roles of the different HIF isoforms in MDSC recruitment, proliferation, and function in the tumor microenvironment requires further study. These studies provide insights into the mechanisms of MDSC migration and accumulation in the tumor and TDLN. Further studies may create a basis for novel immunotherapeutic approaches for the treatment of cancer

Exploring the emerging role of the microbiome in cancer immunotherapy

Abstract The activity of the commensal microbiota significantly impacts human health and has been linked to the development of many diseases, including cancer. Gnotobiotic animal models have shown that the microbiota has many effects on host physiology, including on the development and regulation of immune responses. More recently, evidence has indicated that the microbiota can more specifically influence the outcome of cancer immunotherapy. Therapeutic interventions to optimize microbiota composition to improve immunotherapy outcomes have shown promise in mouse studies. Ongoing endeavors are translating these pre-clinical findings to early stage clinical testing. In this review we summarize 1) basic methodologies and considerations for studies of host-microbiota interactions; 2) experimental evidence towards a causal link between gut microbiota composition and immunotherapeutic efficacy; 3) possible mechanisms governing the microbiota-mediated impact on immunotherapy efficacy. Moving forward, there is need for a deeper understanding of the underlying biological mechanisms that link specific bacterial strains to host immunity. Integrating microbiome effects with other tumor and host factors regulating immunotherapy responsiveness versus resistance could facilitate optimization of therapeutic outcomes

Gold Nanorods Conjugated with Doxorubicin and cRGD for Combined Anticancer Drug Delivery and PET Imaging

<p>A multifunctional gold nanorod (GNR)-based nanoplatform for targeted anticancer drug delivery and positron emission tomography (PET) imaging of tumors was developed and characterized. An anti-cancer drug (<i>i.e.</i>, doxorubicin (DOX)) was covalently conjugated onto PEGylated (PEG: polyethylene glycol) GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor-targeting ligands (<i>i.e.</i>, the <i>cyclo(Arg-Gly-Asp-D-Phe-Cys)</i> peptides, cRGD) and ⁶⁴Cu-chelators (<i>i.e.</i>, <i>1,4,7-</i>triazacyclononane<i>-N, N', N''-</i>triacetic acid (NOTA)) were conjugated onto the distal ends of the PEG arms to achieve active tumor-targeting and PET imaging, respectively. Based on flow cytometry analysis, cRGD-conjugated nanocarriers (<i>i.e.</i>, GNR-DOX-cRGD) exhibited a higher cellular uptake and cytotoxicity than non-targeted ones (<i>i.e.</i>, GNR-DOX) <i>in vitro</i>. However, GNR-DOX-cRGD and GNR-DOX nanocarriers had similar <i>in vivo</i> biodistribution according to <i>in vivo</i> PET imaging and biodistribution studies. Due to the unique optical properties of GNRs, this multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy) and multimodality imaging (PET, optical, X-ray computed tomography (CT), etc.).</p