Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival

Cho, H. R.; Yagita, Hideo; La, Soojin; Lee, E. A.; Kim, J.-E.; Akiba, Hisaya; Kim, J.; Suh, Jae-Hee; Vinay, Dass S.; Ju, Seong‐A; Kim, B.-S.; Mittler, Robert S.; Okumura, Ko; Kwon, Byoung S.

doi:10.1111/j.1432-2277.2004.tb00454.x

Cited by 39 publications

(10 citation statements)

References 45 publications

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“…For instance, CD28- or IL-15-mediated upregulation of 4-1BB combined with agonistic anti-4-1BB monoclonal antibodies or recombinant 4-1BBL could promote antigen-independent survival and expansion of memory CD8 T cells (122, 123); this could be critical for long-term memory against repeated exposure to DFT cells in the wild. Also of particular relevance to the DFT disease is that blockade of 4-1BB:4-1BBL pathways leads to prolonged allograft survival for heart (124), skin (124), eye (125), and intestinal (126) tissues in other species.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

et al. 2017

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Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs) in genes and protein domains that have not been previously reported in any species. This checkpoint molecule analysis and review of salient features for each of the molecules presented here can serve as road map for the development of a Tasmanian devil facial tumor disease immunotherapy. Finally, the strategies can be used as a guide for veterinarians, ecologists, and other researchers willing to venture into the nascent field of wild immunology.

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Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

et al. 2017

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“…These data suggest that 4‐1BB was not the main pathway of escape in the absence of CD28 signaling. Despite the lack of striking effect of the genetic absence of 4‐1BBL, blockade of the pathway has had positive impact on allograft survival in mice, prolonging corneal, intestinal, and cardiac allotransplants . Signaling through 4‐1BB and its ligand therefore clearly play a role in alloimmunity; however, its supporting role in this process has thus far hindered its pathway toward the clinic for control of T‐cell activation, quite distinct from the central role it has played in CAR‐mediated T‐cell activation and subsequent tumor clearance.…”

Section: ‐1bb/4‐1bbl Blockade: More Central To Tumor Immunology Thanmentioning

confidence: 99%

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Kean

Turka

Blazar

2017

Immunological Reviews

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Summary In the past decade, the power of harnessing T cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy’s Yang, and focus on manipulating T cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T cell signaling pathways that are being investigated for tolerance-induction, detailing pre-clinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector versus regulatory T cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.

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“…This expression pattern raises the possibility that 4‐1BB/4‐1BBL interactions may be involved in multiple steps in various innate and adaptive immune responses. The 4‐1BB pathway may also be important for allograft rejection because inhibition with an anti‐4‐1BBL antibody significantly prolongs murine cardiac allograft survival 11 …”

Section: Introductionmentioning

confidence: 99%

Blockade of the 4‐1BB (CD137)/4‐1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival in mice

et al. 2007

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Summary To explore the roles of 4‐1BB (CD137) and CD28 in corneal transplantation, we examined the effect of 4‐1BB/4‐1BB ligand (4‐1BBL) and/or CD28/CD80/CD86 blockade on corneal allograft survival in mice. Allogeneic corneal transplantation was performed between two strains of wild‐type (WT) mice, BALB/c and C57BL/6 (B6), and between BALB/c and B6 WT donors and various gene knockout (KO) recipients. Some of the WT graft recipients were treated intraperitoneally with agonistic anti‐4‐1BB or blocking anti‐4‐1BBL monoclonal antibody (mAb) on days 0, 2, 4 and 6 after transplantation. Transplanted eyes were observed over a 13‐week period. Allogeneic grafts in control WT B6 and BALB/c mice treated with rat immunoglobulin G showed median survival times (MST) of 12 and 14 days, respectively. Allogeneic grafts in B6 WT recipients treated with anti‐4‐1BB mAb showed accelerated rejection, with an MST of 8 days. In contrast, allogeneic grafts in BALB/c 4‐1BB/CD28 KO and B6 CD80/CD86 KO recipients had significantly prolonged graft survival times (MST, 52·5 days and 36 days, respectively). Treatment of WT recipients with anti‐4‐1BB mAb resulted in enhanced cellular proliferation in the mixed lymphocyte reaction and increased the numbers of CD4+ CD8+ T cells, and macrophages in the grafts, which correlated with decreased graft survival time, whereas transplant recipients with costimulatory receptor deletion showed longer graft survival times. These results suggest that the absence of receptors for the 4‐1BB/4‐1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival, whereas triggering 4‐1BB with an agonistic mAb enhances the rejection of corneal allografts.

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Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival

Cited by 39 publications

References 45 publications

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Blockade of the 4‐1BB (CD137)/4‐1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival in mice

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