Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin; Yingst, Ashley; Spellman, Stephen R.; Cooley, Sarah; Verneris, Michael R.; Blazar, Bruce R.; Miller, Jeffrey S.

doi:10.1158/0008-5472.can-16-0839

Cited by 152 publications

(118 citation statements)

References 47 publications

(42 reference statements)

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“…The immune checkpoints may share some common mechanism in the regulation of T-cell function. However, this signaling is different from the previous report that TIGIT signals through ZAP70 and ERK1/2 in NK cells (43). Together, gastric cancer cells inhibit AKT/mTOR pathway in CD8 T cells through upregulating TIGIT expression on CD8 T cells.…”

Section: Discussioncontrasting

confidence: 93%

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

et al. 2017

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The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT þ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNg production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice.Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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Section: Discussioncontrasting

confidence: 93%

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

et al. 2017

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“…These data are consistent with recent in vitro reports that the blockade of the TIGIT pathway can increase NK cell IFNγ secretion and abrogate MDSC-mediated inhibition. [18] Our findings suggest that blockade of checkpoint proteins could enhance efficacy of NK cell adoptive therapies and potentially elicit higher clinical response rates in refractory NHL. [4]…”

Section: Discussionmentioning

confidence: 99%

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Bachanová

Sarhan

DeFor

et al. 2017

Cancer Immunol Immunother

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We report a novel phase 2 clinical trial in patients with poor prognosis refractory NHL testing the efficacy of haploidentical donor NK cell therapy (NK dose 0.5–3.27 × 107 NK cells/kg) with rituximab and IL-2.(clinicaltrials.gov NCT01181258) Therapy was tolerated without graft-versus-host-disease, cytokine release syndrome, or neurotoxicity. Of 15 evaluable patients, 4 had objective responses (26.6%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at the level between 0.6–16 cells/µl. Responding patients had lower levels of circulating host derived Tregs (17±4 vs. 307±152 cells/µL; p=0.008) and myeloid derived suppressor cells (MDSC) at baseline (6.6%±1.4% vs. 13.0%±2.7%; p=0.06) than non-responding patients. Lower circulating Tregs correlated with low serum levels of IL-10 (R2=0.64; p<0.003; n=11), suggestive of an immunosuppressive milieu. Low expression of PD-1 on recipients T cells before therapy was associated with response. Endogenous IL-15 levels were higher in responders than non-responding patients at the day of NK cell infusion (mean±SEM: 30.0±4.0; n=4 vs 19.0±4.0 pg/ml; n=8; p=0.02) and correlated with NK cytotoxicity at day 14 as measured by expression of CD107a (R2=0.74; p=0.0009; n=12). In summary, our observations support development of donor NK cellular therapies for advanced NHL as a strategy to overcome chemoresistance. Therapeutic efficacy may be further improved through disruption of the immunosupressive environment and infusion of exogenous IL-15.

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“…As mentioned previously, TGF-β down-modulates NKG2D expression on NK cells. Recent studies from our group have identified a mechanism by which MDSCs suppress NK activity via direct cell contact[69]. This will be discussed in more detail in a later section.…”

Section: Nk Cell Dysfunction Against Tumor Targetsmentioning

confidence: 99%

“…NK functionality was restored when the NK-MDSC culture was supplemented with a TIGIT-antagonistic antibody. Furthermore, no NK inhibition was observed when NK cells and MDSCs were separated via transwell, indicating cell-to-cell contact is necessary for the NK cell immunomodulation[69]. A recently identified subset of NK cells that arises in cytomegalovirus (CMV) infected individuals demonstrates enhanced secondary responses to previously encountered stimulus not seen in conventional NK cells.…”

Section: Breaking Tolerance Through Checkpoint Blockadementioning

confidence: 99%

Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy

Davis

Vallera

Miller

et al. 2017

Seminars in Immunology

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Natural killer (NK) cells have long been known to mediate anti-tumor responses without prior sensitization or recognition of specific tumor antigens. However, the tumor microenvironment can suppress NK cell function resulting in tumor escape and disease progression. Despite recent advances in cytokine therapy and NK cell adoptive transfer, tumor expression of ligands to NK - expressed checkpoint receptors can still suppress NK mediated tumor lysis. This review will explore many of the checkpoint receptors tumors utilize to manipulate the NK cell response as well as some of the current and upcoming pharmacological solutions to limit tumor suppression of NK cell function. Furthermore, we will discuss the potential to use these drugs in combinational therapies with novel antibody reagents such as bi- and tri-specific killer engagers (BiKEs and TriKEs) against tumor-specific antigens to enhance NK cell-mediated tumor rejection.

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Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

Cited by 152 publications

References 47 publications

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy

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