IAP inhibitors enhance co-stimulation to promote tumor immunity
Michael Dougan,Stephanie K. Dougan,Joanna Slisz,Brant Firestone,Matthew Vanneman,Dobrin Draganov,Girija Goyal,Weibo Li,Weibo Li,Donna Neuberg,Richard S. Blumberg,Nir Hacohen,Nir Hacohen,Dale Porter,Leigh Zawel,Glenn Dranoff +15 more
TLDR
It is found that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.Abstract:
The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.read more
Citations
More filters
Journal ArticleDOI
Cancer immunotherapy comes of age
TL;DR: In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.
Journal ArticleDOI
Combining immunotherapy and targeted therapies in cancer treatment
TL;DR: Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.
Journal ArticleDOI
Targeting IAP proteins for therapeutic intervention in cancer
Simone Fulda,Domagoj Vucic +1 more
TL;DR: The most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist.
Journal ArticleDOI
Prospects for combining targeted and conventional cancer therapy with immunotherapy
Philip Gotwals,Scott Cameron,Daniela Cipolletta,Viviana Cremasco,Adam S. Crystal,Becker Hewes,Britta Mueller,Sonia Quaratino,Catherine Anne Sabatos-Peyton,Lilli Petruzzelli,Jeffrey A. Engelman,Glenn Dranoff +11 more
TL;DR: New insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical response in patients.
Journal ArticleDOI
The secret ally: immunostimulation by anticancer drugs
TL;DR: The molecular and cellular circuitries whereby cytotoxic agents can activate the immune system against cancer, and their therapeutic implications, are discussed.
References
More filters
Journal ArticleDOI
Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity
Glenn Dranoff,Elizabeth M. Jaffee,Audrey J. Lazenby,Paul Golumbek,Hyam I. Levitsky,Katja Brose,Valerie Jackson,Hirofumi Hamada,Drew M. Pardoll,Richard C. Mulligan +9 more
TL;DR: The results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines and the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone.
Journal ArticleDOI
T cell receptor antagonist peptides induce positive selection
Kristin A. Hogquist,Stephen C. Jameson,William R. Heath,Jane L Howard,Michael J. Bevan,Francis R. Carbone +5 more
TL;DR: Results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.
Journal ArticleDOI
NF-κB at the crossroads of life and death
Michael Karin,Anning Lin +1 more
TL;DR: The choice between life and death is one of the major events in regulation of the immune system and a major regulator of such life or death decisions is the transcription factor NF-κB as mentioned in this paper.
Journal ArticleDOI
The b7 family revisited
TL;DR: The roles of the B7:CD28 family members in regulating immune responses are revisited, and the therapeutic potential of these families is discussed.
Journal ArticleDOI
Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Jason D. Fontenot,Jeffrey P. Rasmussen,Luke M. Williams,James Dooley,Andrew G. Farr,Alexander Y. Rudensky +5 more
TL;DR: Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions, and it is shown that expression ofFoxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity.