Ray et al. discovered that Cd69 mRNA levels could be used to differentiate between potent and dysfunctional activation states among intratumoral CD69+CD8+ T cells. CD8 T cells with high Cd69 mRNA and CD69 protein showed increased levels of AP-1 transcription factors, produced potent effector molecules, displayed reduced features of exhaustion, showed enhanced antigen engagement, and superior tumor cell killing in vivo compared to Cd69RNAlowCD69+ cells. Simultaneous Cd69 mRNA and protein expression analysis identified Cd69RNAhighCD69+CD8+ T cells associated with antitumor effector function across human cancers.
Contributed by Shishir Pant
ABSTRACT: Undescribed functional axes may intersect with the trajectory of T cell exhaustion (T(EX)) to contribute to the antitumoral functions of CD8 T cells. By leveraging fluorescent transcriptional reporting of the T cell activation marker Cd69, we defined a classifier for potent versus suboptimal CD69(+) activation states arising from T cell stimulation. In tumors, this delineation provided an additional functional readout among T(EX) subsets, marked by enhanced effector molecule production. The more potent Cd69-TFP(hi) state was the most prominent in a T cell-mediated tumor clearance model, displaying increased engagement and superior tumor cell killing. Simultaneous analysis of gene and protein expression in human head and neck tumors enabled a similar strategy to identify Cd69RNA(hi)CD69(+) cells with enhanced functional features compared with Cd69RNA(lo)CD69(+) cells among intratumoral CD8 T cell subsets. Thus, refining the T cell functional landscape in tumors potentiates the identification of rare, potent effectors that could be leveraged for improving cancer treatment.
Author Info: (1) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 9
Author Info: (1) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (6) ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (8) ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (9) ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. (11) Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. (12) Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. (13) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. (14) Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
