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

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.