PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF

Kearney, Conor J.; Lalaoui, Najoua; Freeman, Andrew J.; Ramsbottom, Kelly M.; Silke, John; Oliaro, Jane

doi:10.1038/cdd.2017.94

Cited by 73 publications

(67 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that TNFR2 was identified here in a pooled screen setting points to a cell-intrinsic function of TNFR2 in enhancing cell death. Intriguingly, a recent study found the birinapant to enhance cell killing via the membrane bound form of TNFα (60). In light of our findings, it will thus be interesting to evaluate a possible role for TNFR2 in these settings and whether sensitivity to SMAC mimetic treatment is correlated with TNFR2 expression.…”

Section: Discussionmentioning

confidence: 58%

Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

Fauster

Rebsamen

Willmann

et al. 2018

Preprint

View full text Add to dashboard Cite

Regulation of cell and tissue homeostasis by programmed cell death is a fundamental process with wide physiological and pathological implications. The advent of scalable somatic cell genetic technologies creates the opportunity to functionally map these essential pathways, thereby identifying potential disease-relevant components. We investigated the genetic basis underlying necroptotic cell death by performing a complementary set of loss-and gain-of-function genetic screens. To this end, we established FADD-deficient haploid human KBM7 cells, which specifically and efficiently undergo necroptosis after a single treatment with either TNFα or the SMAC mimetic compound birinapant. A series of unbiased gene-trap screens identified key signaling mediators, such as TNFR1, RIPK1, RIPK3, and MLKL. Among the novel components, we focused on the zinc transporter SLC39A7, whose knock-out led to necroptosis resistance by affecting TNF receptor trafficking and ER homeostasis. Orthogonal, solute carrier (SLC)-focused CRISPR/Cas9-based genetic screens revealed the exquisite specificity of SLC39A7, among ~ 400 SLC genes, for TNFR1-and FAS-but not TRAIL-R1-mediated responses. The newly established cellular model also allowed genome-wide gain-of-function screening for genes conferring resistance to necroptosis via the CRISPR/Cas9 synergistic activation mediator approach. Among these, we found cIAP1 and cIAP2, and characterized the role of TNIP1 (TNFAIP3-interacting protein 1), which prevented pathway activation in a ubiquitin-binding dependent manner. Altogether, the gain-and loss-of-function screens described here provide a global genetic chart of the molecular factors involved in necroptosis and death receptor signaling, prompting investigation of their individual contribution and potential role in pathological conditions. not peer-reviewed)

show abstract

Section: Discussionmentioning

confidence: 58%

Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

Fauster

Rebsamen

Willmann

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Together, these results suggested that the combination of the Immune Checkpoint Inhibitor (ICI), anti-PD1, and birinapant would be a very effective way to increase CL killing. And indeed, this is what the authors observed [149]. Similarly, Beug and colleagues in an extensive and very detailed study, showed that combining the ICIs, anti-PD1 or anti-Cytotoxic T-Lymphocyte-Associated protein 4 (anti-CTLA-4), with the SM LCL161 greatly increased survival in intra-cranial mouse glioblastoma models and produced durable cures [150].…”

Section: Combination With Immunotherapymentioning

confidence: 64%

“…Upon antigen recognition or NK-activating receptor activation, CLs naturally respond by inducing TNF. Surprisingly, given the data showing the ability of SMs to increase TNF levels, birinapant did not increase T-cell production of TNF [149]. On the other hand, tumor-derived Programmed Death-Ligand 1 (PD-L1) engagement of its receptor, Programmed cell Death protein 1 (PD-1), expressed on CLs, decreased CL production of TNF.…”

Section: Combination With Immunotherapymentioning

confidence: 97%

“…Immunotherapy harnesses the immune system to kill tumors. Kearney et al 2017 showed that the SM birinapant sensitized tumor cells to TNF dependent killing by Cytotoxic Lymphocytes (CLs), both CD8+ T cells and Natural Killer (NK) cells. Upon antigen recognition or NK-activating receptor activation, CLs naturally respond by inducing TNF.…”

Section: Combination With Immunotherapymentioning

confidence: 99%

See 1 more Smart Citation

Future Therapeutic Directions for Smac-Mimetics

Morrish

Brumatti

Silke

2020

Cells

Self Cite

109

118

View full text Add to dashboard Cite

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

show abstract

“…PD-L1 expression on CD11b þ MDSCs also impedes the early adaptive immune response to SMAC mimetic monotherapy (16). Several groups have shown that the induction of effective adaptive antitumor immunity with either radiation or a SMAC mimetic compound requires blockade of the PD-1/PD-L1 immune checkpoint (16,20,49), and Deng and colleagues showed that this was dependent upon TNFa-mediated clearance of CD11b þ Gr-1 þ cells (4). It is certainly plausible that additional therapeutic synergy could be achieved by triple therapy: ART, Debio 1143, and PD-1/PD-L1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Tao

McCall

Wiedemann

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrialderived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.Experimental Design: To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8 þ T cells and TNFa, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFa, or anti-IFNg antibodies. Tumorinfiltrating OVA-specific CD8 þ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFa, IFNg, and IL1b and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.Results: ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8 þ cells, TNFa, and IFNg with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.Conclusions: Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFa, IFNg, and CD8 þ T-cell-dependent manner. This provides a novel strategy to enhance the immunogenicity of ART. The combination of ART and Debio 1143 reduces immunosuppressive cell populations and produces an OVA-specific cytotoxic T-cell response in the tumor microenvironment. A, CD8 þ T lymphocytes primed with OVA-tetramer were quantified in LLC-OVA tumors using flow cytometry, and are expressed as a percentage of CD8 þ cells. IFNg (B) and TNFa (C) expression among OVA þ CD8 þ lymphocytes was determined by flow cytometry. These cells are expressed as a percentage of CD8 þ cells. D, Tumors were analyzed for the MDSC markers CD45/Gr1/CD11b using flow cytometry. CD11b þ Gr-1 þ cells are expressed as a percentage of CD45 þ cells. E, LLC-OVA tumors were assessed for the TAM markers CD45/F4/80/CD11b by flow cytometry. The percentage of TAMs is expressed as a percentage of CD45 þ cells. F, LLC-OVA tumors were assessed for the Treg markers CD4/FOXP3/CD25 by flow cytometry. Tregs are expressed as a percentage of CD4 þ cells. All plots show a representative sample (left) and are expressed as a mean with 5 plotted replicates (right). Statistical differences were assessed using the unpaired Student t test. P values are indicated as follows: Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001.

show abstract

PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF

Cited by 73 publications

References 52 publications

Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

Future Therapeutic Directions for Smac-Mimetics

SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Contact Info

Product

Resources

About