ASH 2018 | Low-dose IL-2 therapy increases CD56bright NK cell receptor expression in patients with chronic graft-versus-host disease

At the 60^th ASH Annual Meeting and Exposition, San Diego, CA, Tomohiro Kubo from Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, presented data on behalf of colleagues from a study evaluating adult patients with active chronic graft-versus-host disease (cGvHD) receiving low-dose interleukin-2 (IL-2) therapy.

Natural killer (NK) cells are innate immune cells that defend against tumor and virus-infected cells. NK cells are heterogeneous and are divided into CD56^bright and CD56^dim subsets depending on surface CD56 expression. CD56^dim NK cells are the predominant subset in peripheral blood and minor subset in lymphoid tissue. They constitute approximately 90% of human peripheral blood NK cells and display high cytotoxicity ex vivo. CD56^bright NK cells are the minor subset in peripheral blood and are predominant in secondary lymphoid tissues; normally representing only 5-10% of circulating NK cells.

However, it has been shown that cytolytic activity of CD56^bright NK cells increases when these cells are stimulated with IL-2. Previous studies from Dana-Farber Cancer Institute, Boston, MA, have demonstrated that daily administration of low-dose IL-2 in patients with cGvHD ameliorates selective expansion of CD4⁺FoxP3⁺Helios⁺ regulatory T cells and CD56^bright NK cells, and reduces clinical symptoms of cGvHD. However, the function of each NK cell subsets treated by extracorporeal photopheresis (ECP) plus low dose IL-2 therapy are not well known.

Kubo T. et al. used single cell mass cytometry (CyTOF) with a panel of 35 metal tagged antibodies on cryopreserved peripheral blood mononuclear cells (PBMC) in order to identify distinct lymphocyte subsets and measure functional status.

Patients and methods

• N = 10 patients
• Median age = 62 years (range, 34–76)
• Median time from transplantation: 697 days (range, 340–2846)
• Patients received ECP for 8 weeks prior to starting daily low dose IL-2
• ECP therapy was administered twice weekly
• Patients received low-dose IL-2 (1x10⁶ IU/m²/day) for 8 weeks
• The analytic panel included 26 cell surface markers and 9 intracellular markers

Key findings

• There were no fluctuations in extracellular or intracellular NK cell markers or quantitative changes in NK cells during the 8 week ECP treatment
• Expression change during low-dose IL-2 vs pre low-dose IL-2 therapy:

	CD56bright	CD56dim
ILT-1	↑	→
NKp30	↑	→
NKp46	↑	→
NKG2D	→	→
ILT-2	No expression	↓
KIR	No expression	→
NKG2A	↑	→
ILT, interleukin therapy; KIR, killer-cell immunoglobulin-like receptor; NK, natural killer

 

• Low dose IL-2 therapy induces predominant increased expression of activating NK receptors in CD56^bright NK cells; in contrast, CD56^dim NK cells were less affected

Doctor Kubo concluded that single cell mass cytometry analysis revealed that “daily low dose IL-2 therapy induces selective expansion, activation and predominant increased expression of activating NK receptors in CD56^bright NK cells. In contrast, CD56^dim NK cells were less affected by IL-2 therapy.”

Functional assays showed that cytolytic activity of CD56^bright NK cells were elevated during low dose IL-2 therapy and exceeded the cytotoxicity of CD56^dim NK cells. In patients receiving low-dose IL-2 after allogeneic transplantation, expanded CD56^bright NK cells may contribute to graft-versus-leukemia (GVL) effect and help prevent relapse after transplant.