Predominant CD8+ cell infiltration and low accumulation of regulatory T cells in immune checkpoint inhibitor-induced tubulointerstitial nephritis

Immune checkpoint inhibitors (ICIs) can contribute significantly to the treatment of many malignancies, including metastatic melanoma. There are three main types of ICIs—antiprogrammed cell death 1 (PD1), antiprogrammed death-ligand 1 (PD-L1), and anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies. Anti-PD1 and anti-PD-L1 antibodies block the PD-1/PD-L1 pathway and induce immune activity against tumors, whereas anti-CTLA-4 antibodies block the CTLA-4/B7 (CD80/CD86) pathway in T cells, leading to the disruption of inhibitory immune signaling. ICIs can activate T cells and exert antitumor effects by blocking either pathway. However, they can also lead to the development of immune related adverse events (irAEs). Approximately 90% of patients undergoing ICI treatment experience irAEs of differing severity. These events can affect any organ, including the skin, gastrointestinal tract, liver, heart, thyroid, adrenal gland, pituitary gland, and kidneys. The most common pathological feature of renal irAEs is tubulointerstitial nephritis (TIN). Lymphocytes are predominant in the tubulointerstitium with ICI-induced TIN, which is consistent with the mechanism underlying the effect of ICIs. Non-ICI drug-induced TIN is also mediated by lymphocytes and is indistinguishable from ICI-induced TIN. However, the pathophysiology differs between the two TIN types, warranting different treatments. Therefore, we compared the clinical and histological features of ICI-induced TIN with those of non-ICI drug-induced TIN.

We included all patients diagnosed with ICI‐induced and non‐ICI drug‐induced TIN between December 2016 and November 2022. All diagnoses were based on clinicopathological information. The ICIs included were PD‐1 and CTLA‐4 inhibitors and their combination. The exclusion criteria were interstitial inflammation secondary to conditions, such as IgG4‐related disease, Sjogren's syndrome, sarcoidosis, bone marrow diseases, and antineutrophil cytoplasmic antibody-associated vasculitis. Thirteen patients from four university hospitals, for whom renal biopsies were available, were included. Baseline clinical and laboratory data and information on medications were collected from digital medical records. Laboratory data included baseline serum creatinine, C‐reactive protein (CRP), urine N‐acetyl‐β‐d‐glucosaminidase, and β2‐microglobulin levels and the urine protein–creatinine ratio at baseline. Renal interstitial inflammatory cell types were investigated using immunohistochemistry. For immunohistochemical analysis, slides were scanned using a virtual slide system (Olympus VS200), and the frequency of positive cells per unit area was determined using the QuPath software (Ver. 0.3.2). The pathological features of ICI-induced TIN were confirmed and compared with those of non-ICI drug-induced TIN.

Age and CRP levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN.

T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI‐induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.