CXCL12 Mediates Immunosuppression in the Lymphoma Microenvironment after Allogeneic Transplantation of Hematopoietic Cells

Abstract

Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigenpresenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance.In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT.

Downregulation of Inflammatory MicroRNAs by Ig-like Transcript 3 Is Essential for the Differentiation of Human CD8+ T Suppressor Cells

“…Although SOCS1 is a negative regulator of cytokine signaling (31,33), DUSP10 acts on the MAPK pathways inhibiting TCR signaling (42). CXCR4, a receptor for the trafficking ligand CXCL12, was shown to contribute to the induction of T cell immunotolerance in mice (43).…”

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

“…18 Bone marrow cells were cultured at 5x10 6 cells/10 mL in the presence of 40 ng/mL granulocyte-monocyte colony-stimulating factor (supernatant from the producer line X63-Hybridom). On days 3 and 5, 10 mL of fresh medium containing granulocyte-monocyte colony-stimulating factor were added.…”

Tumor Microenvironment Macrophage Inhibitory Factor Directs the Accumulation of Interleukin-17-producing Tumor-infiltrating Lymphocytes and Predicts Favorable Survival in Nasopharyngeal Carcinoma Patients

“…The origin of Th17 cells and their biological function in human tumor microenvironments are still under investigation. Mechanistic studies have revealed that many cytokines and chemokines, including CCL5, CCL17, CCL20, CCL22, MCP-1, and IL-6, are expressed at a high level within the tumor microenvironment in association with the accumulation of Th17 cells (3,(11)(12)(13)(14). However, the mechanistic relationships in NPC between the accumulation of Th17 cells, the cytokines released from tumor environments, and tumorigenesis and progression remain unknown.…”