Tumor microenvironment of adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy caused by the human T-cell leukemia virus type 1. Aggressive ATLL is refractory to conventional chemotherapy and has a poor prognosis. Better therapeutic approaches, including cancer immunotherapy, are required to improve survival and prognosis. The genetic landscape of ATLL reveals frequent genetic alterations in genes associated with immune surveillance, including major histocompatibility complex (MHC) class I, CD58 antigen, and programmed cell death ligand 1. Clinicopathological investigations also revealed tumor immunity mechanisms in ATLL, including immune checkpoint molecules, MHC molecules, tumor-associated macrophages, and chemokines. However, the tumor microenvironment of ATLL remains complex because ATLL itself originates from T-cells, usually expressing regulatory T-cell markers. In this review, we discuss the recent literature describing the tumor microenvironment of ATLL.

Keywords: Hematolymphoid Tissues; Infectious; Lymphomas/Lymphoid Leukemias; Lymphoproliferative Disorders; Reactive.

Fig. 1

Immunohistochemistry of MHC class I and class II. A) ATLL cells expressing MHC class I. B) Loss of MHC class I. C) β2M is expressed on ATLL cells. D) Loss of β2M, E) ATLL cells, positive for MHC class II, F) Loss of MHC class II. MHC, major histocompatibility complex; ATLL, adult T-cell leukemia/lymphoma; β2M, beta 2 microglobulin

Fig. 2

Immunohistochemistry of immune checkpoint molecules. A) ATLL cells expressing PD-L1. B) Stromal cells, positive for PD-L1. C) Stromal cells expressing Tim-3. D) OX40L+ stromal cells are observed. ATLL, adult T-cell leukemia/lymphoma; PD-L1, programmed cell death ligand-1; Tim-3, T-cell immunoglobulin mucin-3; OX40L, a ligand for OX40

Fig. 3

Fusions involving CD28. A) Scheme of CD28-CTLA4 and CD28-ICOS fusions. Fusion of the C-terminal domain of CD28 and the N-terminal domain of CTLA-4 or ICOS may interact with CD80 or CD86 on ATLL cells or stromal cells, and convert the CTLA-4- or ICOS-mediated signal to a CD28-mediated co-stimulatory signal. B) ATLL cells strongly expressing CD28. C) CD80 is expressed on ATLL cells. D) Stromal cells positive for CD86. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICOS, inducible co-stimulator; ATLL, adult T-cell leukemia/lymphoma

Fig. 4

Immunohistochemistry of CD47 and SIRPα. A) ATLL cells expressing CD47. B) CD47- ATLL cells. C) Stromal cells positive for SIRPα. D) SIRPα is negative in stromal cells. SIRPα, signal-regulatory protein alpha; ATLL, adult T-cell leukemia/lymphoma

Fig. 5

The microenvironment of ATLL. Scheme summarizing recent findings of the tumor microenvironment of ATLL. Immune evasion from CD8+ T-cells by loss of MHC class I and class II, loss of CD58, and overexpression of PD-L1 has been reported. Loss of MHC class II may be important for immune evasion from CD4+ T-cells. Immune suppression by TAMs, chemokines, and Treg function of ATLL itself was also reported. Interaction between CD80/CD86 and CD28 fusion proteins can mediate continuous CD28-mediated tumor activation. However, some stromal cells express immune checkpoint molecules and/or SIRPα, which play a role in the better prognosis of ATLL patients through an unknown mechanism. ATLL, adult T-cell leukemia/lymphoma; MHC, major histocompatibility complex; PD-L1, programmed cell death ligand-1; TAM, tumor-associated macrophage; Treg, regulatory T-cell; SIRPα, signal-regulatory protein alpha