Redirection to the bone marrow improves T cell persistence and antitumor functions

Abstract

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15–dependent homeostatic expansion and promoted the differentiation of memory precursor–like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.

CXCR4, but not CXCR3, drives CD8+ T‐cell entry into and migration through the murine bone marrow

“…6). Moreover, our data are in agreement with recent findings from Khan et al, who transferred CD8 + T cells into RAG-deficient mice, and observed that the majority of adoptively transferred CD8 T cells inside the calvarial BM migrate at a very low speed, which could be increased by overexpressing CXCR4 [37]. Importantly, although the velocity of CD8 + T cells in the BM may be low, this does not imply that they are all resident in the BM.…”

CD4+FOXP3+ T Cells in Rheumatoid Arthritis Bone Marrow Are Partially Impaired

“…Recent data point to the role of bone marrow T cells in the immune system. BM Tregs seem to be required for optimal control of GVHD post-transplant [40] while redirection to the BM was shown to increase T cell antitumor functions [41].…”

Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors

“…These factors may cause poor trafficking of CAR-T cells to solid tumors. Intensive and extensive studies have been performed to tackle these problems and these include engineering T cells with chemokine receptors (such as CXCR2, CCR2b, CXCR4), incorporation of heparanase to degrade the extracellular matrix (ECM), and regional delivery of CAR-T cells [26][27][28].…”