This schematic depicts a model describing the characteristics of, and possible
connections between, the major CD8+ T cell states in human tumors, as
based on data from20–22,28–31,33,34. Observations from the different studies that support
this model are listed in Supplementary Table S1. In brief, the naïve-like cells
described in non-small-cell lung cancer (NSCLC)29, hepatocellular carcinoma (HCC)28, colorectal cancer
(CRC)31, basal cell
cancer (BCC)30, and
melanoma21 show a
strong resemblance to the (central-)memory populations described by Sade-Feldman
et al. and Clarke et al.22,33. Based on the expression of
granzyme K (GZMK), intermediate expression of inhibitory
molecules, and relatively low clonality, the T lymphocyte population described
in Sade-Feldman et al.22 and
the effector–memory population described in Zhang et al.31 were considered similar to the
pre-dysfunctional cell states observed in melanoma21, HCC28,
and NSCLC29. While additional
research is required to determine their extent of overlap, the tissue resident
memory T (TRM) population described in triple-negative breast cancer
(TNBC)34 and the
HAVCR2+ TRM cells in NSCLC33 are here aligned with the
dysfunctional state described in all other studies. The cell state definitions
from Azizi et al.32 could not
be integrated into the model presented here and the effector–memory
subset reported by Savas et al. may be composed of a mixture of
pre-dysfunctional and cytotoxic cells, based on the combined expression of
GZMK and killer cell lectin-like receptor subfamily G
member 1 (KLRG1)34. In this
model, we propose that the development of (pre-)dysfunctional cell states is
predominantly driven by tumor-specific cues such as tumor antigen recognition
and/or tumor-specific environmental factors (here referred to as tumor
microenvironment (TME)-induced differentiation). Cytotoxic cell states are also
encountered in healthy tissues28,29,31, indicating that the
underlying differentiation process is not strictly tumor-specific (here referred
to as TME-independent differentiation). Cytotoxic effector T cells are depicted
as a population that is most likely developmentally distinct from the cells
along the (pre-)dysfunctional axis, but additional research is required to
clarify whether cytotoxic effector cells indeed originate from a distinct pool
of cells, or whether they are connected to the (pre-)dysfunctional axis in some
situations (as depicted by the dashed two-way arrow). Note that both trajectory
and T cell receptor (TCR) sharing analyses indicate that the pre-dysfunctional
and dysfunctional cells form a continuum of cell states, rather than
well-demarcated populations. The line graph shows approximate levels of
proliferation, CXC-chemokine ligand 13 (CXCL13) expression, and
the expression of inhibitory receptors by pre-dysfunctional, early
dysfunctional, and late dysfunctional CD8+ T cells.
CCR7, CC-chemokine receptor 7; CX3CR1,
CX3C chemokine receptor 1; CTLA4, cytotoxic
lymphocyte-associated antigen 4; FCGR3A, Fcγ receptor
IIIA; IL7R, interleukin 7 receptor; LAG3,
lymphocyte activation gene 3; PDCD1, programmed cell death 1;
PRF1, perforin 1; TCF7, transcription
factor 7.