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Dynamics and specificities of T cells in cancer immunotherapy

Nature Reviews Cancer volume 23, pages 295–316 (2023)Cite this article

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Abstract

Recent advances in cancer immunotherapy — ranging from immune-checkpoint blockade therapy to adoptive cellular therapy and vaccines — have revolutionized cancer treatment paradigms, yet the variability in clinical responses to these agents has motivated intense interest in understanding how the T cell landscape evolves with respect to response to immune intervention. Over the past decade, the advent of multidimensional single-cell technologies has provided the unprecedented ability to dissect the constellation of cell states of lymphocytes within a tumour microenvironment. In particular, the rapidly expanding capacity to definitively link intratumoural phenotypes with the antigen specificity of T cells provided by T cell receptors (TCRs) has now made it possible to focus on investigating the properties of T cells with tumour-specific reactivity. Moreover, the assessment of TCR clonality has enabled a molecular approach to track the trajectories, clonal dynamics and phenotypic changes of antitumour T cells over the course of immunotherapeutic intervention. Here, we review the current knowledge on the cellular states and antigen specificities of antitumour T cells and examine how fine characterization of T cell dynamics in patients has provided meaningful insights into the mechanisms underlying effective cancer immunotherapy. We highlight those T cell subsets associated with productive T cell responses and discuss how diverse immunotherapies might leverage the pre-existing tumour-reactive T cell pool or instruct de novo generation of antitumour specificities. Future studies aimed at elucidating the factors associated with the elicitation of productive antitumour T cell immunity are anticipated to instruct the design of more efficacious treatment strategies.

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Fig. 1: Phenotypes of CD8+ T cells within the native tumour microenvironment.
Fig. 2: Effect of immunotherapies on the T cell repertoire of patients.
Fig. 3: Mechanisms of response to ICB and the T cell subsets involved.
Fig. 4: The phenotypic composition of transferred T cells affects the outcome of adoptive T cell therapy.

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Acknowledgements

G.O. acknowledges N. Cieri for scientific discussions. G.O. was supported by DF/HCC Kidney Cancer SPORE P50 CA101942. C.J.W. acknowledges support from NIH NCI R01CA155010.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Giacomo Oliveira & Catherine J. Wu

  2. Harvard Medical School, Boston, MA, USA

    Giacomo Oliveira & Catherine J. Wu

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Giacomo Oliveira & Catherine J. Wu

  4. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Catherine J. Wu

Authors
  1. Giacomo Oliveira
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  2. Catherine J. Wu
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Contributions

G.O. researched data for the article. Both authors contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Giacomo Oliveira or Catherine J. Wu.

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C.J.W. is an equity holder of BioNTech. G.O. declares no competing interests.

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Nature Reviews Cancer thanks Paul Robbins, who co-reviewed with Sri Krishna; Kellie N. Smith; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Antigenic mimicry

Similarity between different antigens that results in their immune recognition by the same T cells.

Central tolerance

The clonal deletion of autoreactive T cells in the thymus during ontogenesis to create a state in which immune cells are unresponsive to autoantigens.

Cytometry by time of flight

Technique that measures the abundance of metal isotope labels on antibodies and other tags (such as peptide–major histocompatibility complex (MHC) tetramers) on single cells using mass spectroscopy.

Epitope spreading

Also known as antigen spread. The broadening of the immune response from the initially targeted epitope to other epitopes on the same antigen or different antigens.

HLA restrictions

Requirement that T cells recognize antigens only when presented by germline-encoded HLA molecules that are polymorphic and specific for each subject.

Major histocompatibility complex (MHC) multimer

Oligomers of MHC molecules that are loaded with antigenic peptides, tagged with probes and assembled together so that they can provide a measurable signal on T cells once the complex binds to the antigen-specific T cell receptors (TCRs).

Secondary lymphoid organs

Specialized tissues, such as the spleen and lymph nodes, where antigen-presenting cells instruct the activation of mature lymphocytes.

Tandem minigenes

Artificial gene constructs composed of consecutive gene fragments of T cell targets, which can be transfected into antigen-presenting cells to achieve the presentation of encoded epitopes.

Tertiary lymphoid structures

(TLS). Organized aggregates of immune cells that form postnatally in non-lymphoid tissues.

Tumour-associated neoantigens

(TAAs). Antigens encoded by unmutated genes in both normal and cancer cells but that exhibit a preferentially high expression in tumour cells.

Tumour private neoantigens

Antigens arising from mutation of the patient-specific tumour genome that causes tumour cells to express specific proteins that are not expressed on normal cells.

V(D)J recombination

Somatic rearrangement of pre-existing variable, diversity and joining gene segments of the TCR α-chain or β-chain genes, which results in the generation and expression of diverse TCRs in T cells.

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Oliveira, G., Wu, C.J. Dynamics and specificities of T cells in cancer immunotherapy. Nat Rev Cancer 23, 295–316 (2023). https://doi.org/10.1038/s41568-023-00560-y

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