Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSCs). In cancer patients, increased MDSCs correlate with more aggressive disease and a poor prognosis. Expression of 15 immune factors (TGFβ, IL-1β, IL-4, IL-6, IL-10, GM-CSF, M-CSF, IDO, fms-related tyrosine kinase 3 ligand, c-kit ligand, inducible NO synthase, arginase-1, TNF-α, cyclo-oxygenase 2, vascular endothelial growth factor [VEGF]) by MDSC-inducing human solid tumor cell lines was evaluated by RT-PCR. Based upon these data, cytokine mixtures were then tested for their ability to generate suppressive CD33+ cells from healthy donor PBMCs in vitro by measuring their ability to inhibit the proliferation of, and IFN-γ production by, fresh autologous human T cells after CD3/CD28 stimulation. Induced MDSCs were characterized with respect to their morphology, surface phenotype, and gene expression profile. MDSC-inducing cancer cell lines demonstrated multiple pathways for MDSC generation, including overexpression of IL-6, IL-1β, cyclo-oxygenase 2, M-CSF, and IDO. CD33+ cells with potent suppressive capacity were best generated in vitro by GM-CSF and IL-6, and secondarily by GM-CSF + IL-1β, PGE2, TNF-α, or VEGF. Characterization studies of cytokine-induced suppressive cells revealed CD33+CD11b+CD66b+HLA-DRlowIL-13Rα2int large mononuclear cells with abundant basophilic cytoplasm. Expression of inducible NO synthase, TGFβ, NADPH oxidase, VEGF, and/or arginase-1 was also upregulated, and Transwell studies showed suppression of autologous T cells to be contact dependent. Suppressive CD33+ cells generated from PBMCs by GM-CSF and IL-6 were consistent with human MDSCs. This study suggests that these cytokines are potential therapeutic targets for the inhibition of MDSC induction in cancer patients.

Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are identification of likely responders to immunotherapy regimens among individuals with cancer or to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here the immune profiles of six murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to two immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative RT-PCR, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (Treg and MDSC), to analyze intratumoral and draining lymphoid tissues. Tumors stratified as highly or poorly immunogenic, with highly immunogenic tumors showing significantly greater presence of T-cell co-stimulatory molecules and immunosuppression in the tumor microenvironment. An absence of tumor-infiltrating CTL and mature DC was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine +/− DC vaccine immunotherapy was associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.

Breast implant-associated ALCL is a novel manifestation of site- and material-specific lymphoma originating in a specific scar location, presenting a wide array of diverse characteristics and suggesting a multifactorial cause.