T-Cell and NK-Cell Infiltration into Solid Tumors: A Key Limiting Factor for Efficacious Cancer Immunotherapy

Melero, Ignacio; Rouzaut, Ana; Motz, Greg; Coukos, George

doi:10.1158/2159-8290.cd-13-0985

Cited by 368 publications

(310 citation statements)

References 28 publications

(33 reference statements)

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“…Checkpoint inhibitors are only able to unleash antitumor T-cell responses in an immunogenic TME. Therefore, turning an immunosuppressive tumor into an immunogenic tumor is necessary for successful cancer immunotherapy (2). Several combination therapies have been proposed that combine checkpoint inhibitors with other checkpoint inhibitors, inhibitors of suppressive metabolites, vaccines, targeted therapies, cytotoxics, and/or radiotherapy (16).…”

Section: Discussionmentioning

confidence: 99%

“…Insufficient infiltration of T and NK cells into tumors may be a limiting factor for efficacious cancer immunotherapy such as checkpoint inhibition (2). Despite considerable clinical benefit of checkpoint inhibition in various cancers, such as melanoma, non-small cell lung cancer, and renal cell cancer, only a minority of patients even in these indications actually benefit from this treatment.…”

Section: Introductionmentioning

confidence: 99%

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Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

Zboralski

Hoehlig

Eulberg

et al. 2017

Cancer Immunology Research

133

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Immune checkpoint inhibitors promote T cell-mediated killing of cancer cells; however, only a subset of patients benefit from the treatment. A possible reason for this limitation may be that the tumor microenvironment (TME) is immune privileged, which may exclude cytotoxic T cells from the vicinity of cancer cells. The chemokine CXCL12 is key to the TME-driven immune suppression. In this study, we investigated the potential of CXCL12 inhibition by use of the clinical-stage L-RNA-aptamer NOX-A12 (olaptesed pegol) to increase the number of tumor-infiltrating lymphocytes. We used heterotypic tumor-stroma spheroids that mimic a solid tumor with a CXCL12-abundant TME. NOX-A12 enhanced the infiltration of T and NK cells in a dose-dependent manner. NOX-A12 and PD-1 checkpoint inhibition synergistically activated T cells in the spheroids, indicating that the agents complement each other. The findings were validated in vivo in a syngeneic murine model of colorectal cancer in which the addition of NOX-A12 improved anti-PD-1 therapy. Taken together, our work shows that CXCL12 inhibition can break the immuneprivileged status of the TME by paving the way for immune effector cells to enter into the tumor, thereby broadening the applicability of checkpoint inhibitors in cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

Zboralski

Hoehlig

Eulberg

et al. 2017

Cancer Immunology Research

133

View full text Add to dashboard Cite

show abstract

“…Many studies demonstrate low levels of NK cell infiltration in solid tumors. 32,33 Importantly, NK cells in solid tumors are frequently functionally impaired and in certain conditions soluble B7-H6 might contribute to downregulation of the NKp30 receptor. Moreover, alternatively spliced NKp30 isoforms affecting the prognosis of GIST 8 and neuroblastoma patients 9 were described.…”

Section: Discussionmentioning

confidence: 99%

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

et al. 2016

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Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNAmediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.

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“…TGF-β has suppressive effects on effector cells and APCs, whereas IL-10 downregulates expression of co-stimulatory molecules and MHC (49). Furthermore, overexpression of diverse chemokines by the HNSCC tumor cells mediate the recruitment of suppressive myeloid cells, such as myeloidderived suppressive cells (MDSC) and tumor-associated macrophages (TAMs); deregulation of immune cell recruitment limits the anti-tumor immune response (42,50).…”

Section: Immune System and Cancer Developmentmentioning

confidence: 99%

The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications

Economopoulou¹,

Perisanidis²,

Giotakis³

et al. 2016

Ann. Transl. Med.

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Head and neck squamous cell carcinoma (HNSCC) carries a poor prognosis, with low survival rates for advanced stage tumors and minimal improvement in survival trends through the past decades. It is becoming increasingly clear that HNSCC oncogenesis and evolution is characterized by profound immune defects, as cancer cells evade immunosurveillance due to accumulation of genetic mutations and tumor heterogeneity. Improved understanding of the role of the immune system in cancer has led to the identification of novel therapeutic targets, which are being investigated for their potential to provide durable responses. In this review, we will summarize the role of the immune system in HNSCC, the rationale behind immunotherapy strategies and their clinical applications.

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T-Cell and NK-Cell Infiltration into Solid Tumors: A Key Limiting Factor for Efficacious Cancer Immunotherapy

Cited by 368 publications

References 28 publications

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications

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