Synergistic induction of cancer-related immunosuppression by β2-adrenergic stress mediators and P38MAPK inflammatory pathway

Psychological stress has been implicated in promoting cancer recurrence and progression, but the magnitude of this effect and underlying mechanism remain unclear. In attempt to address this controversy, we have evaluated the impact of stress on molecular and cellular components of cancer Immune-surveillance and tested the hypothesis that the impact of stress in promoting tumor-associated immune suppression is context-dependent

IL-18-based combinatorial adjuvants promote the NK-DC-mediated production of the CCR7 ligand CCL19 in lymph nodes from cancer patients

Effective accumulation and interaction of mature dendritic cells (DCs) and naïve T cells within lymph nodes (LNs), driven by the CCR7-CCL19/CCL21 axis, are critical for the induction of adaptive T cell immunity. Human natural killer (NK) cells activated by IL-18 exhibit unique 'helper' activity in promoting productive DC-T cell interactions, inducing dendritic cell (DC) maturation and the type-1-polarization of DC-primed T cell responses. Here we demonstrate that such IL-18-induced 'helper' NK cells uniquely induce high DC production of CCL19 in a TNFα and IFNγ-mediated mechanism, dependent on secondary NK cell stimulation with the additional inflammatory signals IFNα, IL-15, IL-12, or IL-2. Helper NK cell-activated DCs promote efficient CCR7-mediated recruitment of naïve CD8+ T cells, and subsequently induce their expansion and acquisition of granzyme B. Using an ex vivo explant culture system of LNs isolated from colorectal cancer patients, we further demonstrate enhanced expression of CCL19 in human tumor-associated lymphoid tissue induced by treatment with helper NK cell-stimulating factors. Our data indicate the ability of two-signal-activated 'helper' NK cells to promote LN production of the DC- and naïve/memory T cell-attracting chemokine CCL19, and provide rationale for therapeutic application of IL-18-containing 'combinatorial adjuvants' to promote the induction of anti-tumor immunity

Selective costimulation by IL-15R/IL-15, but not IL-2R/IL-2, allows the induction of high numbers of tumor-specific CD8+ T cells by human dendritic cells matured in conditions of acute inflammation

Conventional dendritic cells (DC) are believed to rely on membrane-bound IL-2Rα to trans-present soluble IL-2 and costimulate T cell activation and expansion. In contrast, Langerhans cells have been shown to use membrane-bound IL-15Rα/IL-15 complex to activate T cells. Here we show that, while the expansion of tumor-specific CD8+ T cells by DC matured in the presence of chronic inflammatory mediators (PGE2, TNFα IL-1β, IL-6) fully depends on expression of IL-2Rα, CD8+ T cell expansion induced by IL-12p70-producing DC matured by interferon's and Toll-Like receptor ligands (type-1-polarized; DC1) is both more effective and independent of IL-2Rα expression. While DC1-expressed IL-15Rα promotes the expansion of tetramer-specific CD8+ T cells, their secreted levels of IL-12p70 determines the degree of CD8+ T cell functionality as evidenced by tumor antigen-specific release of IFNγ and TNFα. In accordance with the in vivo advantage of utilizing an IL-2-independent pathway of costimulation of tumor-specific T cells, in a retrospectively analyzed cohort of patients with metastatic malignant melanoma treated with cyclophosphamide and tumor-antigen transfected DCs (NCT00978913) we observed a highly significant inverse relation between overall survival and expression of IL-2Rα on DC vaccine products (p = 0.009). The differential usage of IL-2Rα/IL-2 versus IL-15Rα/IL-15 pathways by subsets of DCs helps to explain the role of different types of inflammation in memory formation, exhaustion of CD8+ T cell responses and progression of cancer. Furthermore, ex vivo induction of IL-15Rα/IL-15 dependent signaling might improve adoptive T cell therapies targeting tumors with well-defined and undefined tumor rejection antigens

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy

Zinc in innate and adaptive tumor immunity

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order

Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells: Helper Role of CD8+ T Cells in the Development of T Helper Type 1 Responses

Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of “T helper (Th)” signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood– or peripheral blood–isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-γ at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I–presented epitopes by antigen-specific CD8+ T cells results in the TNF-α– and IFN-γ–dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I–restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I–presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections

Ex-Th17 Foxp3+ T cells - a novel subset of Foxp3+ T cells induced in cancer

Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg misbalance associates with inflammation.\ud \ud We demonstrate that in addition to natural (n)Treg and induced (i)Treg cells developed from naïve precursors, Th17 cells are a novel source of Foxp3+ cells by converting into ex-Th17 Foxp3+ cells, and this helps to reconcile the contradictory information about the relevance in particularly of Th17 subset in immune surveillance.\ud \ud We identified IL-17A+Foxp3+ double-positive and ex-IL-17-producing IL-17A-Foxp3+ T cells to be the underlying mechanism of immune regulation in mesenchymal stem cell-mediated prolonged allograft survival. Further, we identified accumulation of IL17A+Foxp3+ and ex-Th17 Foxp3+ cells in tumor bearing mice, indicating progressive direct Th17-into-Treg cell conversion as a novel phenomenon in cancer.\ud \ud Moreover, we determined the importance of the Th17 cell plasticity for tumor induction and/or progression in ROR-g-/- mice. Our data indicate that RORgt is required not only for Th17 development, but also for effective Treg cell induction. TGF-b1 induced Foxp3 expression was reduced in ROR-g -/- cells. Further, tumor bearing ROR-g-/- mice showed significantly less Foxp3+ Treg cells, but higher IFNg+ Tcells compared to wild type animals.\ud \ud Increased infiltration of IL17+ and FoxP3+ CD4+ T cells in the human ovarian cancer ascites, with the presence of a distinct IL17+FoxP3+ subset, and a significant correlation between tumor-associated Th17 and Treg cells demonstrates the existence of Th17-Foxp3+ T cell inter-relationship in cancer patients.\ud \ud Yin-yang of IL17+ and Foxp3+ is important principle for improved clinical approaches targeting responses against self, allo and/or neo-self

Development and stability of Th17 cells in ovarian cancer requires nitric oxide and endogenous NOS2 activity in cancer-associated CD4+ T cells

Th17 cells play reciprocal roles in different forms and at different stages of cancer. We report that the presence of Th17 cells in ovarian cancer ascites correlates with local expression of nitric oxide synthase-2 (NOS2). Furthermore, the development of RORγt+IL-23R+IL-17+ Th17 cells from human naive-, memory- or tumor-infiltrating CD4+ T cells critically depends on NO and endogenous NOS2 induced in CD4+ T cells by Th17-inducing cytokines (IL-1β/IL-6/IL-23) or by cancer-associated IL-1β/IL-6/IL-23/NO-producing MDSCs. Inhibition of NOS2 or its downstream cGMP/cGK signaling pathway abolishes de novo induction of Th17 cells. Moreover, even short-term blockade of NOS/cGMP suppresses the IL-17 production by established Th17 cells isolated from ovarian cancer patients, demonstrating the novel key role of NOS/cGMP in Th17 cell physiology and providing for new therapeutic targets to manipulate Th17- and NOS/cGMP-associated immunity in precancerous lesions and advanced cancer

Restraint and Social Isolation Stressors Differentially Regulate Adaptive Immunity and Tumor Angiogenesis in a Breast Cancer Mouse Model

The ability of stress to induce immune suppression is widely recognized, but the mechanisms underlying the effects of stress on the adaptive immune system during tumor progression are not completely understood. To study the effect of stress on the immune system in vivo, we used a preclinical immunocompetent mouse model bearing 4T1 mammary adenocarcinoma cells. Mice were randomized into 4 groups, including social isolation (SI), acute restraint stress (aRRS), chronic restraint stress (cRRS), or no stress (NS). We found that SI significantly decreased the number of tumor-bearing mice still alive at the end of protocol (28 days), compared to NS mice. Although we did not detect significant changes in primary tumor volume, we observed a significant increase in the endothelial marker CD31 in primary tumors of SI mice and in lung metastases in SI and RRS mice. Survival decline in SI mice was associated with significant decreases in splenic CD8 cells and in activated T cells. From a mechanistic standpoint, RRS increased expression of FOXP3, CXCL-10, and granzyme B in mouse tumors, and the effects were reversed by propranolol. Our data demonstrate that various forms of stress differentially impact adaptive immunity and tumor angiogenesis, and negatively impact survival.</jats:p