Immune Checkpoint Inhibition in Solid Organ Transplantation

Immune checkpoint inhibitors are monoclonal antibodies that release endogenous brakes on T cells, thereby enhancing anti-tumour immunity. Agents targeting programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have transformed oncology but pose a dilemma in solid organ transplant recipients. In these patients, restoration of T-cell activity may not discriminate between malignant and donor antigens, precipitating allograft rejection. Optimising the balance between tumour control and graft tolerance has become a central challenge. Recent work has elucidated clonal dynamics of alloreactive T cells, explored the modulation of co-inhibitory pathways to foster long-term tolerance and investigated adjunctive regimens to uncouple anticancer efficacy from organ toxicity. Advances in biomarker monitoring and combinatorial immunosuppression hold promise for safely extending checkpoint blockade to transplant recipients with malignancy.

Research from Nature Portfolio

Recent studies have used high-throughput T-cell receptor sequencing to trace alloreactive CD8+ clones in a renal transplant patient treated with anti-PD-1 therapy for melanoma. Findings revealed a rapid expansion of donor-reactive T cells bearing a distinct transcriptomic signature in peripheral blood and the rejected allograft, but not in tumour tissue, underlining the unintended amplification of alloresponses during cancer immunotherapy. In parallel, work combining PD-1 blockade with mTOR inhibition demonstrated that addition of sirolimus can maintain anti-tumour cytotoxicity while suppressing graft-directed T-cell expansion. This co-treatment preserved regulatory T-cell populations, reduced eosinophilia and allowed sustained interferon-γ-mediated tumour control, suggesting a viable strategy to dissociate graft rejection from checkpoint blockade efficacy.

Immune Checkpoint Inhibition in Solid Organ Transplantation publication trend

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

Technical terms

Immune checkpoint inhibitor: A therapeutic antibody that blocks inhibitory receptors or ligands on T cells to enhance immune responses against tumours.

Programmed cell death protein 1 (PD-1): An inhibitory receptor on activated T cells that limits immune responses upon binding PD-L1 or PD-L2.

Programmed death-ligand 1 (PD-L1): A ligand expressed on tumour cells and antigen-presenting cells that engages PD-1 to suppress T-cell activity.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4): An inhibitory receptor on T cells that competes with costimulatory signals and attenuates early T-cell activation.

Alloreactive T cells: T lymphocytes that recognise non-self human leucocyte antigen (HLA) on transplanted tissue, driving graft rejection.

mTOR inhibitor (sirolimus): An immunosuppressive agent targeting the mammalian target of rapamycin pathway to inhibit T-cell proliferation and modulate immune tolerance.

References

1. Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy. Nature Communications (2023).
2. Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation. Nature Communications (2019).
3. Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma. Frontiers in Immunology (2023).
4. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. Journal for ImmunoTherapy of Cancer (2019).