Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours

Keywords

• tumour microenvironment

• tissue-resident memory T cells (TRM)

• exhausted T cells (TEX)

Main Findings

The study investigates the role of CD8+ T cell subsets, specifically tissue-resident memory T cells (TRM) and exhausted T cells (TEX), within the tumor microenvironment across various human cancers. The central question addressed in this manuscript is whether and how TRM and TEX co-exist in tumors, how these populations can be functionally and molecularly distinguished, and what implications their differences have for cancer prognosis and responses to immunotherapy.

• Previously existing TRM gene signatures fail to distinguish TRM from TEX in tumors, as tumor TEX in co-opt a residency program. The authors define new transcriptomic signatures that allow their identification across several human tumor types.

• Analysis of different human cancer datasets demonstrated that TRM signature enrichment, although associated with positive prognosis, does not predict nor correlate with clinical response to immune checkpoint blockade (ICB). In contrast, TEX show predictive value: tumors enriched for a TEX gene signature show better ICB response, and tumors with high neoantigen load may preferentially promote TEX formation

• Using a combination of human datasets and mouse models, the authors demonstrate that within the tumor TRM and TEX represent clonally distinct T cell populations but share a common progenitor with TEX and other tumor infiltrating T cells.

• Presence of antigen and TCR signaling strength are critical determinants of TRM vs TEX fate in tumors, and intratumoral bona fide TRM are likely tumor agnostic bystanders, low affinity tumor-specific cells or not in contact with cognate antigen, while but can be converted to TEX in antigen-rich tumors. On the other hand, absence of antigen can lead to TRM phenotype acquisition by TEX-like cells

Limitations & Suggestions

• The manuscript provides a coherent and well-structured experimental rationale, in which the differences between TEX and TRM and their respective antigen-driven differentiation pathways are logically developed and easy to follow. However, the manuscript contains an extensive number of figure panels, some of which are not fully described in the text or are not referred to at all. Providing clearer descriptions and condensing some panels where possible could improve the clarity and readability.

• There are some inconsistencies in the terminology/definition of T cell subsets (e.g. TEX, GNLYlo PD-1hi, TEX-like populations defined as CD39+ CD103− with Toxhi versus Toxlo expression, and TPROG). A more standardized nomenclature would help readers follow the analyses.

• The human cohorts are not sufficiently described (for example with respect to matched sampling, age distribution, or pre-treatment status), and inclusion of this metadata should be provided for full transparency.

• While in humans the majority of TRM cells are reported to be CD69+ CD103−, the human data analyzed in this manuscript does not include a dedicated analysis of CD103− TRM/TEX populations. Addressing this subset could provide a more comprehensive view of the human TRM compartment.

Significance/Novelty

• The definition of practical and transferable transcriptional signatures that distinguish TEX and TRM is novel and important, providing a valuable resource for future research and potential patient stratification.

• Conceptually, the manuscript proposes a model in which tumor-specific TRM may contribute to long-term immune surveillance in this tissue, tumor-agnostic TRM have superior functional properties but are not targeted by ICB, and TEX are the primary mediators of tumor clearance in response to ICB. This highlights the complementary roles of these cells in the context of cancer immunity and may pave the way for novel therapeutic approaches that harness the functional capacities of both cell types.

Credit

Reviewed by Laura Marie Gail and Lea Heinzl as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.