TY - JOUR TI - Differential expression of CD49a and CD49b determines localization and function of tumor-infiltrating CD8+ T cells AU - Melssen, Marit M. AU - Lindsay, Robin S. AU - Stasiak, Katarzyna AU - Rodriguez, Anthony B. AU - Briegel, Amanda M. AU - Cyranowski, Salwador AU - Rutkowski, Melanie R. AU - Conaway, Mark R. AU - Melief, Cornelis JM AU - Burg, Sjoerd H. van der AU - Eyo, Ukpong AU - Slingluff, Craig L. AU - Engelhard, Victor H. T2 - Cancer Immunology Research AB - 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, while 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 impacts 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. DA - 2021/01/01/ PY - 2021 DO - 10.1158/2326-6066.CIR-20-0427 DP - cancerimmunolres.aacrjournals.org J2 - Cancer Immunol Res LA - en SN - 2326-6066, 2326-6074 UR - https://cancerimmunolres.aacrjournals.org/content/early/2021/02/22/2326-6066.CIR-20-0427 Y2 - 2021/02/24/00:46:52 ER -