Using the Kaede genetic model and photoactivation to directly label tumor immune cells in situ, Li, Tuong, and Dean et al. provided the first in vivo analysis of T cell recruitment, retention, and egress over time in a tumor model. CD8+ T cells retained within the tumors rapidly (<72 hrs) developed an exhausted phenotype. The TCF-1+ CD8+ T cell niche in tumors was highly dynamic, with constant recruitment of new cells, differentiation to effector cells, and egress of the “stem-like” cells back to lymphoid tissue. PD-L1 blockade reinvigorated exhausted CD8+ T cells retained within the tumor and enhanced effector functions of newly recruited CD8+ T cells to enhance the antitumor responses.
Contributed by Shishir Pant
ABSTRACT: Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.