Abstract
Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide–MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.
Key points
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Productive T cell-mediated immunity is dependent on the ability of T cells to traffic to the site where they are needed and adapt to the new tissue site.
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Not all T cells interpret cues from their tissue microenvironment in the same way — T cell differentiation state shapes the way external cues are sensed by the cell.
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Although most exhausted CD8+ T cell subsets have an inflexible epigenetic framework that limits their adaptability to certain types of microenvironments, they can adopt some resident memory-like features to persist in tissues.
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Primary tumours represent aberrant versions of the original host tissue and place strains on T cells, including a high antigen load, an abnormal vasculature, hypoxia, nutrient deprivation and an abnormal extracellular matrix.
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Metastasis involves tumour cells from one tissue invading and establishing residence in another tissue, and the physiology of the destination tissue can shape both the new tumour microenvironment and the immune response.
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T cell migration and adaptability to different types of microenvironments represent therapeutic opportunities to improve outcomes during cancer immunotherapy.
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Acknowledgements
We apologize to colleagues whose work was not cited in our Review due to space constraints. This work was supported by a grant from the US National Institutes of Health (National Cancer Institute (NCI), K08-CA256044 — J.M.S.).
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Glossary
- Adjuvant setting
-
Therapies that are given after the primary cancer treatment (for example, after major surgery to remove the tumour) and that are intended to keep the cancer from returning.
- Aryl hydrocarbon receptor
-
(AHR). A ligand-activated transcription factor that integrates environmental, dietary, metabolic and microbial cues within a cell to modulate immune responses in settings of both health and disease. This receptor acts in a ligand-specific, cell-type-specific and context-specific manner.
- Cancer immunotherapy
-
A type of treatment that targets the host immune system to fight cancer.
- Central memory T (TCM) cells
-
A population of memory T cells that is anatomically restricted to spleen, lymph nodes and blood, and that uses the same trafficking molecules as naive T cells (namely CCR7, CD62L and LFA1) to circulate through these organs. TCM cells are thought to retain the highest level of plasticity in terms of re-differentiating into other T cell subsets and possess the greatest degree of longevity of the memory subsets.
- Checkpoint inhibitors
-
A type of immunotherapy in which monoclonal antibodies are used to block major immunological ‘checkpoints’ for immune activation. These checkpoint molecules generally refer to inhibitory receptors expressed by T cells, including cytotoxic T lymphocyte-associated antigen 4 (CTLA4), PD1, lymphocyte activation gene 3 (LAG3), T cell immunoglobulin mucin 3 (TIM3) and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), though in some cases the ligand for these receptors (for example, PD-L1) are the target instead of the receptor itself.
- Chemokine receptors
-
A family of G protein-coupled receptors involved in cellular migration and activation.
- Effector memory T cells
-
A population of memory T cells that surveys nonlymphoid tissue and blood following antigen clearance. Effector memory T cells are thought to be a recirculating population; this differentiates them from canonical tissue-resident memory T cells, which permanently establish residency in a tissue. Effector memory T cells are generally thought to be less long-lived and less plastic than central memory T cells.
- Effector T cell
-
T cell that has recently encountered antigen and has fully differentiated into an activated state. This differentiation process includes proliferation and acquisition of effector functions, such as inflammatory cytokine production and cytotoxicity.
- Epigenetic landscape
-
The broad set of heritable changes in gene expression that occur independently of changes to the DNA sequence (for example, DNA methylation, histone modifications). The epigenetic landscape refers to the entire set of accessible chromatin regions in a cell, which dictates cell lineage, fate and effector potential by controlling which genes can actually be expressed.
- Epithelial-to-mesenchymal transition
-
(EMT). A complex, biological process that allows polarized epithelial cells that normally interact with a basement membrane to convert into a mesenchymal state, enabling enhanced migratory capacity, invasiveness, increased production of extracellular matrix components and increased resistance to apoptosis. This allows the cell to detach from the basement membrane and migrate away from the epithelial layer. This process occurs during normal embryonic development, tissue generation, organ fibrosis and wound healing. This process is notably exploited by cancer cells and is a major pathway involved in tumour invasiveness and metastasis.
- Exhausted T (TEX) cells
-
A type of T cell dysfunction that is common in chronic infection and cancer. Following activation and differentiation, chronic antigen exposure causes TEX cells to progressively lose effector activity and effector potential, marked by decreased proliferation, cytokine production and cytotoxicity. TEX cells also express high levels of co-inhibitory receptors and the transcription factor TOX.
- Extravasation
-
The process of cellular migration from the blood vessels into a tissue.
- Fibrosis
-
The process by which fibrous connective tissue accumulates in response to tissue injury or damage.
- Hypoxia
-
A tissue environment in which oxygen levels are low.
- Immunosuppressive cytokines
-
Broadly refers to a class of cytokines capable of suppressing or dampening host immune responses. These cytokines are often overexpressed in cancer and can include IL-10 and TGFβ.
- Immunosuppressive leukocyte populations
-
Leukocyte populations that are capable of countering pro-inflammatory immune responses and often lead to immunotherapy resistance in the context of cancer. These populations include regulatory T cells and some populations of tumour-associated macrophages and neutrophils.
- Integrins
-
A family of transmembrane receptors that is critical for facilitating cell–cell adhesion and/or cell–extracellular matrix adhesion. Integrins are heterodimers. In humans, there are at least 18 different α-subunits and 8 different β-subunits, which can heterodimerize to form 24 heterodimers. Integrins bind ligands that are members of the immunoglobulin superfamily.
- Memory T cell
-
Antigen-experienced T cell that persists long-term after antigen clearance. There are multiple subtypes of memory T cells classified broadly based on location, including central memory T cells (restricted to secondary lymphoid organs), effector memory T cells (found recirculating through tissues) and tissue-resident memory T cells (permanently retained within a tissue). Memory T cells can reacquire effector properties upon antigen re-encounter more rapidly than naive T cells.
- Naive T cells
-
T cells that have not yet become activated by cognate peptide–MHC presented by professional antigen-presenting cells. Naive T cells are anatomically restricted to the spleen, lymph nodes and blood, using the trafficking molecules CCR7 (a chemokine receptor binding CCL19 and CCL21), CD62L (a selectin binding 6-sulfo sialyl Lewis X oligosaccharides present on high endothelial venules) and LFA1 (an integrin that binds ICAM1) to mediate entry into these sites.
- Neoadjuvant setting
-
Broadly refers to therapies that are given before the primary cancer treatment (for example, before major surgery to remove the tumour).
- Non-neoplastic tissue
-
A tissue that has not transformed and/or does not contain a tumour.
- Progenitor TEX (TPEX) cells
-
A subset of exhausted T (TEX) cells that expresses high levels of the transcription factor TCF1 and lower levels of co-inhibitory receptors, and that retains higher proliferative capacity than other TEX cell subsets. The TPEX cell subset contains stem-like properties, being able to divide to give rise to more TPEX cells and to differentiate into other TEX cell subsets including the terminally exhausted TEX cell subset. This subset preferentially proliferates in response to PD1 checkpoint blockade.
- Reverse translation
-
An approach in which observations are made from clinical samples that are hypothesis generating, and then those hypotheses are tested in preclinical mouse models in which mechanisms can be interrogated.
- Selectins
-
A family of cell surface adhesion molecules that is important for leukocyte trafficking. Selectins are single-chain, transmembrane glycoproteins that bind fucosylated, sialylated or sulfated ligands.
- Sphingosine 1-phosphate receptor 1
-
(S1PR1). A G protein-coupled receptor that binds the phospholipid sphingosine 1-phosphate (S1P). S1PR1 regulates T cell migration between tissues and circulatory fluids. S1PR1 has a critical role in T cell egress from lymph nodes and tissues by enabling T cells to sense high levels of S1P in efferent lymphatics and blood. S1PR1 is directly antagonized by CD69 at the cell surface, so if CD69 is expressed, T cells fail to upregulate S1PR1 and respond to S1P.
- Terminally exhausted TEX cell
-
A type of exhausted T (TEX) cell that is terminally differentiated, expressing low to no TCF1 and high levels of co-inhibitory receptors including PD1, T cell immunoglobulin mucin 3 (TIM3), lymphocyte activation gene 3 (LAG3) and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). Terminally exhausted TEX cells have poorer proliferative capacity and inflammatory cytokine production than other TEX cell subsets, but do retain a heightened ability to kill target cells. Terminally exhausted TEX cells cannot differentiate into other TEX cell subsets and are poorly proliferative in response to PD1 checkpoint blockade.
- Tertiary lymphoid structures
-
Induced ectopic lymphoid structures that develop in nonlymphoid tissues and/or tumours. Tertiary lymphoid structures are organized aggregates of immune cells that resemble secondary lymphoid organs, but are not encapsulated. They are generally associated with inflamed tissues and have been documented in cancer, autoimmunity and chronic inflammatory disorders.
- Tissue-resident memory T (TRM) cell
-
A memory T cell that establishes residency within a given tissue (that is, once it enters, it does not leave). TRM cells have been described in both lymphoid and nonlymphoid tissue. The surface markers CD69 and CD103 have both been associated with TRM cells, though not all TRM cells express these markers.
- Vascular anergy
-
A phenomenon that occurs when blood vessels receive continual vascular endothelial growth factor (VEGF) stimulation, causing them to become unable to upregulate inflammatory chemokines and integrin ligands to permit leukocyte trafficking.
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Schenkel, J.M., Pauken, K.E. Localization, tissue biology and T cell state — implications for cancer immunotherapy. Nat Rev Immunol 23, 807–823 (2023). https://doi.org/10.1038/s41577-023-00884-8
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DOI: https://doi.org/10.1038/s41577-023-00884-8
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