Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade

Abstract

Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Nivolumab treatment resulted in rapid expansion of predominant ATLL clones. Clonal analysis of the peripheral blood of patients 1 and 3 before (A) and after (B) nivolumab therapy comparing probe-capture sequencing for HTLV-1 proviral integration sites with TCR gene rearrangement of β locus (TRB; supplemental Table 2) and γ locus (TRG; supplemental Table 1). Clones < 1% of total reads are shown in white.

Figure 2.

ATLL clones that rapidly expanded after PD-1 blockade carry mutations commonly found in ATLL. Mutations present in patient PBMCs before (A) and after (B) nivolumab therapy. Percentage of reads is for mutant over total number of reads for each gene segment. Mutations that increased in abundance after nivolumab are shaded green, the mutation that decreased after nivolumab is shaded pink, and the mutation present only after nivolumab is shaded red in the table. The schematic diagram below the table shows the role of each gene product in T-lymphocyte signaling pathways (green, mutations in patient 1; red, mutations in patient 3).

Figure 3.

Circulating ATLL cells posttreatment resemble tumor-infiltrating Tregs. RNAseq was used to profile gene-expression changes caused by nivolumab treatment. The color bar indicates the fold change (after/before) for each gene. Selected genes represent genes associated with Tregs and lymphocyte checkpoint pathways that increase or decrease more than twofold after treatment with nivolumab.

Figure 4.

Posttreatment ATLL cells in patients 1 and 3 represent distinct Treg subtypes. RNAseq was used to profile gene-expression changes caused by nivolumab treatment. The color bar indicates the fold change (after/before) for each gene. Selected genes represent genes associated with peripheral blood cell signaling pathways that increase or decrease more than twofold after treatment with nivolumab and differ between patient 1 and patient 3.

Figure 5.

Mechanisms by which PD-1 blockade could promote rapid progression of ATLL.