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Evaluation of regulatory T-cells in cancer immunotherapy: therapeutic relevance of immune checkpoint inhibition

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Abstract

The evolution of the complex immune system is equipped to defend against perilous intruders and concurrently negatively regulate the deleterious effect of immune-mediated inflammation caused by self and nonself antigens. Regulatory T-cells (Tregs) are specialized cells that minimize immune-mediated inflammation, but in malignancies, this feature has been exploited toward cancer progression by keeping the antitumor immune response in check. The modulation of Treg cell infiltration and their induction in the TME (tumor microenvironment) alongside associated inhibitory molecules, both soluble or membranes tethered in the TME, have proven clinically beneficial in boosting the tumoricidal activity of the immune system. Moreover, Treg-associated immune checkpoints pose a greater obstruction in cancer immunotherapy. Inhibiting or blocking active immune checkpoint signaling in combination with other therapies has proven clinically beneficial. This review summarizes the ontogeny of Treg cells and their migration, stability, and function in the TME. We also elucidate the Treg-associated checkpoint moieties that impede effective antitumor activity and harness these molecules for effective and targeted immunotherapy against cancer nuisance.

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Abbreviations

APC:

Antigen-presenting cell

CCL2:

Chemokine (C–C motif) ligand 2

CCl7:

Chemokine (C–C motif) ligand 7

CCR4:

C–C chemokine receptor type 4

CCR4:

C–C chemokine receptor type 4

CD25:

Interleukin-2 receptor alpha chain

CD7:

Cluster of differentiation 7

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

CXCL12:

C-X-C motif chemokine ligand 12

FR4:

Folate receptor 4

GITR:

Glucocorticoid-induced tumor necrosis factor receptor-related protein

ICOS:

Inducible T-cell COStimulator

IL-10:

Interleukin 10

IL-2:

Interleukin-2

IL-35:

Interleukin 35

LAG-3:

Lymphocyte-Activation Gene 3

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed death ligand-1

PGE2:

Prostaglandin E2

TdLNs:

Tumor-draining lymph node

TGF-β :

Transforming growth factor beta

TIGIT:

T-cell immunoreceptor with immunoglobulin and ITIM domains

TIM-3:

T-cell immunoglobulin mucin 3

TME:

Tumor microenvironment

Treg/Tregs:

Regulatory T-cell(s)

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Acknowledgements

RS thanks the Indian Council of Medical Council Research (ICMR), India (2021-12946/CMB-BMS), for a senior research fellowship.

Funding

This work was supported by IOE grant No. R/Dev/D/IOE/Incentive/2021–22/32275 to Partha Pratim Manna by Banaras Hindu University (BHU).

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  1. Immunobiology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, UP, 221005, India

    Ranjeet Singh, Prateek Srivastava & Partha Pratim Manna

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Singh, R., Srivastava, P. & Manna, P.P. Evaluation of regulatory T-cells in cancer immunotherapy: therapeutic relevance of immune checkpoint inhibition. Med Oncol 41, 59 (2024). https://doi.org/10.1007/s12032-023-02289-y

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