Immune Checkpoint Inhibition in Hematologic Malignancies

Immune checkpoint inhibition has emerged as a transformative strategy in the treatment of haematologic malignancies, harnessing the body’s own immune system to recognise and eliminate malignant cells. Central to this approach are inhibitory receptors such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expressed on T lymphocytes, whose engagement by ligands on tumour cells or within the tumour microenvironment (TME) blunts antitumour immunity. In classical Hodgkin lymphoma, blockade of PD-1 interactions has yielded high response rates in relapsed or refractory disease, prompting regulatory approvals. In contrast, responses in non-Hodgkin lymphomas, acute leukaemias and multiple myeloma have been more variable, reflecting heterogeneity in antigen presentation, checkpoint ligand expression and immune infiltrate composition. Resistance mechanisms are multifactorial, involving up-regulation of alternative checkpoints such as lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), aberrant signalling pathways within tumour cells, and suppressive stromal elements. Current research focuses on refining patient selection through predictive biomarkers including PD-L1 expression and T-cell exhaustion signatures, and on combining checkpoint inhibitors with targeted therapies, epigenetic modulators or cellular therapies such as chimeric antigen receptor (CAR) T cells to overcome resistance. These strategies underscore the global significance of immune checkpoint blockade as a precision immunotherapy platform with potential to improve outcomes across a spectrum of blood cancers.

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Immune Checkpoint Inhibition in Hematologic Malignancies publication trend

The graph below shows the total number of articles in immune checkpoint inhibition in hematologic malignancies across all publications each year (not limited to Nature Index journals).

Technical terms

PD-1: An inhibitory receptor on activated T cells that limits immune responses upon engagement by its ligands.

PD-L1: A ligand expressed on tumour and immune cells that binds PD-1 to suppress T-cell activity.

CTLA-4: A checkpoint receptor on T cells that competes with the costimulatory receptor CD28 for ligand binding, down-modulating T-cell activation.

LAG-3: A T-cell checkpoint receptor that binds MHC class II and contributes to T-cell exhaustion and immune regulation.

Tumour microenvironment (TME): The complex milieu of stromal cells, immune cells, extracellular matrix and soluble factors surrounding a tumour, which influences immune surveillance and therapy response.

References

1. Blockade of PD-1 and LAG-3 expression on CD8+ T cells promotes the tumoricidal effects of CD8+ T cells. Frontiers in Immunology (2023).
2. Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art. International Journal of Molecular Sciences (2024).
3. Resistance mechanisms of immune checkpoint inhibition in lymphoma: Focusing on the tumor microenvironment. Frontiers in Pharmacology (2023).
4. Checkpoint inhibitors in hematological malignancies. Journal of Hematology & Oncology (2017).