Mesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-γ (MPγ). Tracking analysis and electron microscopy indicated that the average size of MP was 120 nm, and they showed a round shape. MP exhibited ATPase, nucleotidase and esterase activity, indicating they are enzymatically active. MP and MPγ did not physically interact with T cells and had no effect on CD4+ and CD8+ T cells proliferation. However, MP and MPγ selectively bound to monocytes and decreased the frequency of pro-inflammatory CD14+CD16+ monocytes by induction of selective apoptosis. MP and MPγ increased the percentage of CD90 positive monocytes, and MPγ but not MP increased the percentage of anti-inflammatory PD-L1 monocytes. MPγ increased mRNA expression of PD-L1 in monocytes. These data demonstrate that MP have immunomodulatory properties and have potential as a novel cell-free therapy for treatment of immunological disorders.

Survival of gastrointestinal cancer remains dismal, especially for metastasized disease. For various cancers, especially melanoma and lung cancer, immunotherapy has been proven to confer survival benefits, but results for gastrointestinal cancer have been disappointing. Hence, there is substantial interest in exploring the usefulness of adaptive immune system education with respect to anti-cancer responses though vaccination. Encouragingly, even fairly non-specific approaches to vaccination and immune system stimulation, involving for instance influenza vaccines, have shown promising results, eliciting hopes that selection of specific antigens for vaccination may prove useful for at least a subset of gastrointestinal cancers. It is widely recognized that immune recognition and initiation of responses are hampered by a lack of T cell help, or by suppressive cancer-associated factors. In this review we will discuss the hurdles that limit efficacy of conventional cancer therapeutic vaccination methods (e.g., peptide vaccines, dendritic cell vaccination). In addition, we will outline other forms of treatment (e.g., radiotherapy, chemotherapy, oncolytic viruses) that also cause the release of antigens through immunogenic tumor cell death and can thus be considered unconventional vaccination methods (i.e., in situ vaccination). Finally, we focus on the potential additive value that vaccination strategies may have for improving the effect immunotherapy. Overall, a picture will emerge that although the field has made substantial progress, successful immunotherapy through the combination with cancer antigen vaccination, including that for gastrointestinal cancers, is still in its infancy, prompting further intensification of the research effort in this respect.

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Terminal T-cell exhaustion poses a significant barrier to effective anti-cancer immunotherapy efficacy with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL-2 receptor (IL-2R) - STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL-2R-intermediate Janus kinase (JAK) 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) which potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited anti-tumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared to both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy.