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

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: Marit M Melssen, Robin S Lindsay, Katarzyna Stasiak, Anthony B Rodriguez, Amanda M Briegel, Salwador Cyranowski, Melanie R Rutkowski, Mark R Conaway, Cornelis J M Melief, Sjoerd H van der Burg, Ukpong Eyo, Craig L Slingluff Jr, Victor H Engelhard
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 9 Issue 5 Pg. 583-597 (05 2021) ISSN: 2326-6074 [Electronic] United States
• PMID: 33619119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antigens, CD
• Integrin alpha1
• Integrin alpha2
• NR4A1 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antigens, CD (metabolism)
• Breast Neoplasms (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Female
• Humans
• Immunologic Memory (genetics)
• Integrin alpha1 (metabolism)
• Integrin alpha2 (metabolism)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Male
• Melanoma (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Nuclear Receptor Subfamily 4, Group A, Member 1 (metabolism)
• Tumor Microenvironment