Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets

Abstract

Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation ⁺ (VISTA ⁺), programmed cell death 1 ⁺ (PD-1 ⁺), T cell immunoglobulin and mucin-domain-containing-3 ⁺ (Tim-3 ⁺), T cell immunoreceptor with Ig and ITIM domains ⁺ (TIGIT ⁺) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA ⁺ and PD-1 ⁺ T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1 ⁺ and TIGIT ⁺ T cells than the patients without, and PD-1 ⁺CD3 ⁺%, PD-1 ⁺CD4 ⁺%, PD-1 ⁺Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1 ⁺ Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT ⁺ T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA ⁺ and PD-1 ⁺ T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1 ⁺ and TIGIT ⁺ T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.