Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy

Sun, Lillian; Clavijo, Paúl E.; Robbins, Yvette; Patel, Priya; Friedman, Jay; Greene, Sarah; Das, Rita; Silvin, Chris; Waes, Carter Van; Horn, Lucas A.; Schlom, Jeffrey; Palena, Claudia; Maeda, Dean Y.; Zebala, John A.; Allen, Clint

doi:10.1172/jci.insight.126853

Cited by 184 publications

(136 citation statements)

References 58 publications

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“…Only with the addition of anti-PD1 therapy are reductions in tumor burden achieved, which is what we observed in the combination therapy group (SX-682 plus anti-PD1). Notably, CXCR2 antagonists have previously been reported to enhance the efficacy of anti-PD1 antibodies in various solid tumor models in mice (31)(32)(33). This line of experimentation was included here to provide clear evidence that neutrophil antagonism results in the relocation of CD8 + T cells from the tumor periphery into the malignant portions of tumor and restores the IFN-γ signature, indicative of favorable immune responses.…”

Section: Discussionmentioning

confidence: 90%

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC

Kargl¹,

Zhu²,

Zhang³

et al. 2019

JCI Insight

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132

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Section: Discussionmentioning

confidence: 90%

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC

Kargl¹,

Zhu²,

Zhang³

et al. 2019

JCI Insight

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132

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“…PD-L1 expression on myeloid cells is sufficient and may even be required for immunosuppression mediated by PD-pathway signaling(30, 32). We and others have demonstrated that elimination of myeloid cells or inhibition of their trafficking into tumors has little effect as a monotherapy but enhances T cell cell-based immunotherapy when used in combination(33-35). A natural extension of the work presented here is to combine PD-L1 CAR haNKs with different T cell or NK cell-based immunotherapies to explore if reduction in myeloid cell populations can enhance responses to other immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

Robbins

Greene

Friedman

et al. 2020

Preprint

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27Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations 28 pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the 29 presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) 30 engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and 31 murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. 32 Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth 33 inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of 34 xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced 35 levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood 36 from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 3 Background 53 T cell-based immunotherapy, such as immune checkpoint blockade or adoptive T cell transfer, is 54 limited by the ability of T cells to detect major histocompatibility complex (MHC)-presented antigen by 55 tumor cells. Through selective immune pressure during tumorigenesis and progression and genomic 56 instability, subpopulations of tumor cells acquire mutations that lead to defective type II interferon (IFN) 57 responses and altered antigen processing and presentation (1, 2). The presence of these mutations predicts 58 failure to respond to immune checkpoint blockade and adoptive T cell transfer immunotherapy(3-6). 59Natural killer (NK) cell-based immunotherapy may overcome genetic mechanisms of resistance 60 to T cell-based immunotherapy through antigen-and MHC-independent recognition of malignant cells. 61NK cells express germ-line receptors that are either stimulatory or inhibitory, and the summation of these 62 signals determines activation status (7). NK-92 cells, derived from a Non-Hodgkin's lymphoma patient, 63 can be continuously expanded in culture and following irradiation, can be safely administered in high 64 doses to patients with cancer(8-10). High-affinity NK (haNK) cells are NK-92 cells engineered to express 65 endoplasmic reticulum-retained IL-2(11), have demonstrated potent effector function in numerous pre-66 clinical models(12, 13), and following irradiation, can also be safely administered in high doses to 67 patients(14). haNKs represent an "off the shelf" NK cellular therapy available for pre-clinical and clinical 68 study. However, barriers within the tumor microenvironment that further limit T cell activation and 69 function such as the presence of immunosuppressive myeloid cells also can limit the activation and 70 function of NK cells (15, 16). Thus, addressing the presence of immunosuppressive myeloid cell 71 populations in the periphery and tumor microenvironment of patients with cancer is likely to be required 72 for effective NK cell-bas...

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“…By targeting CXCR2, MDSC populations were reduced and reported to decrease metastasis, promote T-cell infiltration into the tumours, improve anti-PD1 therapy, and extend survival in pancreatic cancer [159]. Additionally, CXCR2 antagonists against MDSCs have been shown to enhance the therapeutic efficacy of PD-1 immunotherapy, T-cell transfer, and chemotherapy [150,213,214].…”

Section: Blockade Of Mdsc Migrationmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

333

272

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The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

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Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy

Cited by 184 publications

References 58 publications

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

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