Differential Expression of CD49a and CD49b Determines Localization and Function of Tumor-Infiltrating CD8+ T Cells

Cancer Immunology Research, vol. 9, pp. 583–597

Abstract

Abstract CD8+ T-cell infiltration and effector activity in tumors are correlated with better overall survival of patients, suggesting that the ability of T cells to enter and remain in contact with tumor cells supports tumor control. CD8+ T cells express the collagen-binding integrins CD49a and CD49b, but little is known about their function or how their expression is regulated in the tumor microenvironment (TME). Here, we found that tumor-infiltrating CD8+ T cells initially expressed CD49b, gained CD49a, and then lost CD49b over the course of tumor outgrowth. This differentiation sequence was driven by antigen-independent elements in the TME, although T-cell receptor (TCR) stimulation further increased CD49a expression. Expression of exhaustion markers and CD49a associated temporally but not mechanistically. Intratumoral CD49a-expressing CD8+ T cells failed to upregulate TCR-dependent Nur77 expression, whereas CD69 was constitutively expressed, consistent with both a lack of productive antigen engagement and a tissue-resident memory-like phenotype. Imaging T cells in live tumor slices revealed that CD49a increased their motility, especially of those in close proximity to tumor cells, suggesting that it may interfere with T-cell recognition of tumor cells by distracting them from productive engagement, although we were not able to augment productive engagement by short-term CD49a blockade. CD49b also promoted relocalization of T cells at a greater distance from tumor cells. Thus, our results demonstrate that expression of these integrins affects T-cell trafficking and localization in tumors via distinct mechanisms, and suggests a new way in which the TME, and likely collagen, could promote tumor-infiltrating CD8+ T-cell dysfunction.

Authors 13

1. Marit Martina Melssen Aachen 3Department of Medical Oncology Oncode Institute

   Leiden University Medical Center · University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

   3Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands

2. Robin S. Lindsay

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

3. Katarzyna Stasiak

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

4. Anthony B. Rodriguez

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

5. Amanda M. Briegel

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

6. Salwador Cyranowski

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

7. Melanie R. Rutkowski

   University of Virginia

   Affiliation as printed

   1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

   2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia

8. Mark R. Conaway

   University of Virginia

   Affiliation as printed

   4Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia

9. Cornelis J.M. Melief Aachen 3Department of Medical Oncology Oncode Institute 5ISA Pharmaceutical

   Leiden University Medical Center · ISA Pharmaceuticals (Netherlands)

   Affiliation as printed

   3Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands

   5ISA Pharmaceutical, Leiden, the Netherlands

10. Sjoerd H. van der Burg Aachen 3Department of Medical Oncology Oncode Institute

    Leiden University Medical Center

    Affiliation as printed

    3Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands

11. Ukpong B. Eyo

    University of Virginia

    Affiliation as printed

    6Department of Neuroscience, University of Virginia, Charlottesville, Virginia

12. Craig Lee Slingluff

    University of Virginia

    Affiliation as printed

    1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

    7Department of Surgery, University of Virginia, Charlottesville, Virginia

13. Víctor H. Engelhard corresponding

    University of Virginia

    Affiliation as printed

    1Carter Immunology Center, University of Virginia, Charlottesville, Virginia

    2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia