Concurrent fusions of CD28 with CTLA4 and ICOS were identified in 3 of 8 Japanese patients with ATLL <50 years old.
Activation of CTLA4-CD28 depends on cell-autonomous and non-autonomous interactions that are targetable with CTLA4 blockade.
Adult T-cell leukemia/lymphoma (ATLL) in Japan presents at a median age of 70 and only 5% of patients are age <50. We conducted RNA and targeted DNA sequencing of 8 ATLL from Japanese patients <50 and identified 3 (37.5%) with both CTLA4-CD28 and ICOS-CD28 fusions. Mutations of PLCG1, PRKCB and STAT3, which were frequent in other ATLL sequencing studies, were not identified. Differential expression analysis identified the negative checkpoint molecule LAG3 as the most downregulated gene among cases with the fusions. Immunohistochemistry demonstrated expression of CD80 and CD86, the ligands for CTLA4/CD28/ICOS, on ATLL cells and tumor-associated macrophages, respectively. Expression of CTLA4-CD28 in Ba/F3 cells conferred cytokine-independent growth when co-cultured with Raji cells that express CD80 and CD86. Growth was associated with recruitment of the p85 subunit of PI3 kinase to CTLA4-CD28 and phosphorylation of AKT and ERK. A CTLA4-blocking antibody reduced cytokine-independent growth in a dose-dependent manner. Together, these results suggest that young Japanese ATLL cases have a unique biology dependent on cell-nonautonomous interactions that drive CD28 signaling. Assessment for CD28 fusions and treatment with CTLA4 blockade should be considered in younger patients with relapsed/refractory ATLL.