You et al. developed a “live biopsy” approach based on two-photon imaging in mice, then in human tonsil and tumor samples, to investigate the dynamics of T cell movement in the TME, and linked these results with phenotypic and genotypic T cell analyses. T cell speed varied, as did the time of engagement with myeloid or tumor cells. Tumor cell density and extent of exhaustion emerged as key markers, inversely and directly, respectively, of more motile cells. Although exhausted cells demonstrated upregulation of co-inhibitory receptors and reduced effector phenotype, genes related to cell mobility were upregulated, supporting a program of active surveillance.
Contributed by Ed Fritsch
ABSTRACT: Intratumoral T cells that might otherwise control tumors are often identified in an 'exhausted' state, defined by specific epigenetic modifications and upregulation of genes such as CD38, CTLA-4 and PD-1. While the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors as residence time increases and they progress towards exhaustion, we elaborated a non-stimulatory live-biopsy method for real-time study of T cell behaviors within individual patient tumors. Using two-photon microscopy, we studied native CD8 T cells interacting with APCs and cancer cells in different micro-niches of human tumors, finding that T cell speed was variable by region and by patient and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8 T cell motility and exhausted T cell state that corresponds to observations made in mouse models where exhausted T cells move faster. Our study demonstrates T cell dynamic states in individual human tumors and supports the existence of an active program in 'exhausted' T cells that extends beyond incapacitating them.
Author Info: (1) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (2) Department of Pathology, University of California, San Fra
Author Info: (1) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (2) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (3) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (4) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (5) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (6) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (7) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America. (8) Department of Pathology, University of California, San Francisco (UCSF), San Francisco, United States of America.
