Next Article in Journal
The Diverse Functions of Non-Essential Amino Acids in Cancer
Next Article in Special Issue
Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer
Previous Article in Journal
SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib
Previous Article in Special Issue
Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities
Article Menu

Export Article

Open AccessArticle

CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies

1
King’s College London, School of Cancer and Pharmaceutical Studies, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
2
Department of Clinical Immunology and Allergy, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK
3
Department of Immunology, Eastbourne Hospital, East Sussex BN21 2UD, UK
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 674; https://doi.org/10.3390/cancers11050674
Received: 8 April 2019 / Revised: 7 May 2019 / Accepted: 10 May 2019 / Published: 14 May 2019
(This article belongs to the Special Issue The Role of Integrins in Cancer)
  |  
PDF [4148 KB, uploaded 14 May 2019]
  |  

Abstract

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors. View Full-Text
Keywords: CAR-T; immunotherapy; αvβ6; integrin; homing; chemokine receptor; solid tumor; cancer; chimeric antigen receptor; T-cell CAR-T; immunotherapy; αvβ6; integrin; homing; chemokine receptor; solid tumor; cancer; chimeric antigen receptor; T-cell
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Whilding, L.M.; Halim, L.; Draper, B.; Parente-Pereira, A.C.; Zabinski, T.; Davies, D.M.; Maher, J. CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies. Cancers 2019, 11, 674.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top