IL-27 is a heterodimeric cytokine comprised of IL-27p28 and EBI3. As a relatively new member of the IL-12 family, the biological mechanisms associated with the role of IL-27 in the immune response are ambiguous, displaying both proinflammatory and suppressive functions that seem to be dependent on the disease model. A recent report demonstrates that pharmacological blockade of IL-27p28 alleviates graft-versus-host disease (GVHD) in mice. However, the specific role of the IL-27Rα/gp130 signaling complex that forms the IL-27 receptor (IL-27R) on T cells has not been well characterized in the context of allogeneic hematopoietic stem cell transplantation (allo-HCT). Here, we demonstrate that IL-27Rα expression on T cells exacerbates GVHD after allo-HCT, which was consistent across 3 different MHC- mismatched murine models of allo-HCT. Expression of IL-27Rα on T cells was required for acquisition of optimal Th1 effector function and subsequent inhibition of Th2 and T regulatory subsets after allo-HCT. Furthermore, administration of IL-27significantly increased mortality after allo-HCT; suggesting that the suppressive functions linked to IL-27 in T cell responses may be relatively modest in this model. Hence, IL-27Rα signaling on T cells promotes the development of GVHD.
Sorafenib and sunitinib are multiple tyrosine kinase inhibitors. Both of them have been approved by the US FDA in the treatment of patients with malignancies. In order to develop an effective and clinically useful chemoimmunotherapy modality against hepatocellular cancer (HCC), we investigate their tumoricidal and immune modulatory effect in the setting of HCC. In vitro experiments suggested that sunitinib and sorafenib both induced HCC cell apoptosis at an equivalent level, but stronger suppressive function to cell proliferation was detected in sorafenib. Correspondingly, treatment of tumor-bearing mice with sorafenib led to the suppression of tumor growth to a larger extent than sunitinib. Flow cytometry showed that treatment with sunitinib, not sorafenib, significantly reduced the frequency of regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) in tumor-bearing mice; and allowed splenic lymphocytes to produce equivalent levels of IFN-γ and TNF-α in response to vaccination as that in wild type mice. This activation was not detected in control and sorafenib-treated tumor mice. In addition, treatment of tumor-bearing mice with sunitinib followed by adoptive transfer of tumor antigen-specific CD8+ T cells and immunization resulted in the additional suppression to tumor growth compared to sunitinib monotherapy. These results imply treatment with sunitinib, not sorafenib, is able to prevent tumor-induced immunotolerance and activate antitumorimmunity. Our data suggest that sunitinib may be a preferable chemotherapeutic agent to use in combination with immunotherapy for the treatment of HCC.
Vitamin A is an essential micronutrient that participates in a wide range of biological processes. Retinoic acid (RA) is an active metabolite of vitamin A that functions as an immune regulator. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is characterized by extensive inflammation arising from an alloimmune response involving various host and donor immune cells. Since vitamin A affects different immune cell lineages and regulates an array of immune responses, vitamin A, and more specifically retinoic acid, is likely to influence the incidence and/or severity of GVHD. Indeed, recent preclinical and clinical data support this concept. In this review, we briefly summarize recent advances in our understanding of the potential role of vitamin A in modulating GVHD risk after allogeneic HSCT.
Immunotherapeutic treatments for malignant cancers have revolutionized the medical and scientific fields. Lymphocytes engineered to display chimeric antigen receptor (CAR) molecules contribute to the exciting advancements that have stemmed from a greater understanding of cell structure and function, biological interactions, and the unique tumor microenvironment. CAR T cells circumvent the unique immune evasion capability of tumors by acting in a major histocompatibility complex (MHC) independent manner. Various factors contribute to the efficacy of CAR therapy, including CAR structure, gene transfer strategies, in vitro culture system, target selection, and preconditioning regimens. While recent clinical trials have shown promising success, cytotoxicity and other various challenges need to be addressed before CAR therapy can reach its full clinical potency. This review will discuss factors associated with CAR therapeutic success and the difficulties that continue to be a focus of research around the world.
Adoptive T cell transfer (ACT) can mediate objective responses in patients with advanced malignancies. There have been major advances in this field, including the optimization of the ex vivo generation of tumor-reactive lymphocytes to ample numbers for effective ACT therapy via the use of natural and artificial antigen presenting cells (APCs). Herein we review the basic properties of APCs and how they have been manufactured through the years to augment vaccine and T cell-based cancer therapies. We then discuss how these novel APCs impact the function and memory properties of T cells. Finally, we propose new ways to synthesize aAPCs to augment the therapeutic effectiveness of antitumor T cells for ACT therapy.
Transplantation of donor-derived allogeneic hematopoietic cells causes increased survival in patients suffering from various blood cancers and other hematologic and immunologic diseases. However, this health benefit is limited to certain patients. One major complication is graft-versus-host disease (GVHD) that occurs when donor-derived immune cells recognize host cells/tissues as foreign and perpetrate subsequent destruction. Cytokines are a major class of effector molecules that are involved in GVHD pathogenesis. Proinflammatory cytokines released by activated immune cells including T cells lead to the onset of GVHD. T cell depletion (TCD) is an effective approach for GVHD prevention. Several immune suppressive drugs are also used to treat GVHD. However, these prophylactic and treatment strategies often lead to an immune compromised state that increases the risk for infection and cancer relapse. Considering the adverse effects of TCD and overall immune suppression, more selective managements such as approaches targeting proinflammatory cytokines have emerged as a promising strategy to control GVHD. Therefore, this work is dedicated to review recent development in the studies of cytokines and their future implication in GVHD therapy.
Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investigation to reduce GVHD. However, broad application of this approach may require standardization of Treg expansion methods and dosing. Inducible Tregs (iTregs) can be seamlessly generated, but controversial pre-clinical findings and phenotype instability have hampered their translation into the clinic. Here, we review the current biological differences between nTregs and iTregs, as well as their effects on GVHD and graft-versus-leukemia (GVL) responses. We conclude by exploring the idea of combinational cellular therapies for the prevention of GVHD and preservation of GVL.
Cell, the basic unit of life depends for its survival on nutrients and thereby energy to perform its physiological function. Cells of lymphoid and myeloid origin are key in evoking an immune response against "self" or "non-self" antigens. The thymus derived lymphoid cells called T cells are a heterogenous group with distinct phenotypic and molecular signatures that have been shown to respond against an infection (bacterial, viral, protozoan) or cancer. Recent studies have unearthed the key differences in energy metabolism between the various T cell subsets, natural killer cells, dendritic cells, macrophages and myeloid derived suppressor cells. While a number of groups are dwelling into the nuances of the metabolism and its role in immune response at various strata, this review focuses on dynamic state of metabolism that is operational within various cellular compartments that interact to mount an effective immune response to alleviate disease state.
Granzyme B (GzmB) is a key cytotoxic molecule utilized by T cells to kill pathogen-infected cells or transformed tumor cells. Previous studies using allogeneic hematopoietic cell transplantation (allo-HCT) murine models showed that GzmB is required for CD8+ T cells to cause graft-versus-host disease (GVHD). However, our recent study demonstrated that GzmB-mediated damage of CD8+ T cells diminished their graft-versus-tumor (GVT) activity. In this study, we examined the role of GzmB in GVT effect mediated by conventional CD4+CD25- T cells (CD4+ Tcon). GzmB-/-CD4+ Tcon cells exhibited decreased GVT activity compared to wild-type (WT) CD4+ Tcon cells, suggesting that GzmB is required for the optimal GVT activity of CD4+ Tcon cells. On the other hand, GzmB-/- CD4+CD25+ regulatory T cells were as suppressive as WT regulatory T cells in suppressing GVT activity, which is consistent with our previous report showing that GzmB is not required for regulatory T cell-mediated suppression of GVHD. These results demonstrate that GzmB causes opposite impacts on GVT effect mediated by CD4+CD25- versus CD8+ T cells. Interestingly, GzmB-/- total T cells exhibited GVT activity equivalent to that of WT total T cells, suggesting that the opposite impacts of GzmB on the GVT effect of CD4+CD25- versus CD8+ T cells may neutralize each other, which can only be observed when an individual T cell subset is examined. Importantly, these differential roles suggest that targeting GzmB in selective T cell subsets may have the potential to enhance the beneficial GVT effect.
Immune cell-derived cytotoxic pathways have been implicated in antitumor immune responses. The goal of this study is to characterize how these cytotoxic pathways influence ovarian cancer development. We have utilized the TgMISIIR-TAg transgenic mouse model which expresses the transforming SV40 TAg in the ovary, leading to spontaneous development of ovarian tumors that closely mimic human epithelial ovarian cancer. To test how perforin (Prf1), granzyme B (GzmB) and interferon-gamma (IFNg) impact tumor occurrence and progression, we bred the TgMISIIR-TAg transgene into Prf1-/-, GzmB-/-, and IFNgR1-/- mice. The transgenic females developed peritoneal tumors at 9-15 weeks and succumbed at 184 ± 37 days of age with 100% penetrance (n=41). Knockout of these cytotoxic genes does not affect tumor occurrence. However, loss of function in the IFNg signaling pathway significantly expedited tumor progression with all of the IFNg R1-/- TgMISIIR-TAg females succumbing to tumor outgrowth at 167 ± 27 days of age (p=0.0074, n=24). In contrast, loss of function of Prf1 or GzmB did not significantly impact tumor progression and host survival. Since tumor cells in the IFNg R1-/- TgMISIIR-TAg mice are IFNg R1 deficient, we used the implantable MOSEC (mouse ovarian surface epithelial cell) tumor line to validate that IFNg R signaling in host immune cells but not in tumor cells impacts tumor progression. Indeed, when the IFNg -responsive MOSEC cells were inoculated, IFNg R1-/- mice exhibited significantly higher tumor burden compared to WT mice. Furthermore, a MOSEC-splenocyte co-culture system confirmed that IFNg R1-/- immune cells were less effective than WT immune cells in controlling MOSEC tumor growth in vitro. Together, these results indicate that the IFNg R signaling pathway plays an important role in restraining murine ovarian tumor progression.
