The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?

Abstract

Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.

Keywords: AKI (acute kidney injury); CTLA-4; PD-1-PDL-1 axis; gut microbiome; immune checkpoint inhibitors; immunosenescence and inflammaging; mTOR inhibitor; renal cell cancer (RCC).

Figure 1

Effect of ICIs on T lymphocytes. In the tumor microenvironment, professional APCs, such as dendritic cells processed specific tumor peptides (TAA) and complexed them to MHC molecules. Then, APC migrated to T cell-dependent areas of tumor draining lymph node and presented TAA to naïve or quiescent T cells. In the immune synapse between resting T cell and APC, the lymphocytes activation is dependent by two signals. The first is mediated by the binding of TAA to T-cell receptor (TCR). The second signal could be activatory in the case of binding of T cell-CD28 to co-stimulatory CD80/CD86 or inhibitory. The latter is mediated by the binding of T cell-CTLA-4 to the same CD80/CD86 APC molecules. Therefore, CTLA-4 and CD28 compete for the binding to CD80/CD86 proteins. The CTLA-4 signaling will lead to T cell anergy by inhibiting the T naïve activation and clonal expansion. The anti-CTLA-4 blocking by monoclonal antibodies as ipilimumab restore CD28 pro-activatory signaling and result in effective anti-tumor T lymphocyte responses. In peripheral tissues, the activated T cell can be de-activated by the binding of PD-L1 (or PD-L2, not shown) expressed on tumor cells, organ cells or other immune cells to effector T cell- PD-1 receptor. The anti-PD-1 or anti-PD-L1 blocking by monoclonal antibodies (as Nivolumab, Pembrolizumab for PD-1 or Atezolizumab for PD-L1) ipilimumab restore CD28 pro-activatory signaling and restore effective anti-tumor T lymphocyte responses. APC, Antigen Presenting Cells; MHC-Ag, Major Histocompatibility Complex with tumor antigen; CTLA-4, Cytotoxic T-Lymphocyte Antigen 4; PD-1, Programmed cell death protein 1; PD-L1, Programmed death-ligand 1.

Figure 2

Mechanisms of ICIs-associated AKI. The proposed mechanisms underlying ICIs-induced AKI include: Re-activation of drug specific T cells: T cell primed by different drugs (e.g. previous or concomitant antibiotics, PPIs, or NSAIDs) became latent over the time; however they can be re-activated by ICIs, leading to loss of tolerance; Loss of tolerance versus self-antigens: the formation, the selection and proliferation of a clone of self-reactive T-cells, the auto-reactive T cell could activated self-reactive B cells leading to auto-antibody release, that to renal injury; Off Target Effect: the upregulation of PD-L1 on renal tubular epithelial cells can lead to kidney damage by effector T lymphocytes infiltration resulting in acute tubulointerstitial nephritis, Pro-inflammatory cytokines: ICIs promote the migration and activation of effector T cells in renal tissue, the infiltration of other immune cells as B cells together with pro-inflammatory cytokines release as CXCL10, TNFα, IL-6 that contribute to the generation of an inflammatory milieu, leading to renal damage.