T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours

Abstract

The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that the forced expression of the C-X-C chemokine receptor type 6 (CXCR6, whose ligand is highly expressed by human and murine pancreatic cancer cells and by tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell-adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained antitumoral activity and prolonged animal survival only when co-expressing CXCR6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.

Harnessing the chemokine system to home CAR-T cells into solid tumors

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Figure 2 Co-opting chemokine receptor axes to enhance trafficking of CAR-T cells into solid tumors Many tumors derived from different tissue origins share similar patterns of chemokine expression, raising the possibility of enhancing CAR-T cell infiltration into a diverse array of cancers using key chemokine/chemokine receptor axes. Chemokine receptors that have been utilized to guide T cell trafficking into solid tumors and specific anatomical niches include CXCR1, 66 CXCR2, 64 , 65 , 66 , 68 , 69 , 70 CXCR4 113 ( NCT04727008 ), CXCR6, 114 CCR2, 115 , 116 , 117 CCR4, 118 , 119 CCR8, 120 and CX3CR1. 121 Furthermore, CAR-T cells may be modified to express CCL19 and CCL21 to promote recruitment of endogenous DCs and T cells into tumors.

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“… 130 , 131 Transmembrane CXCL16 mediates cell adhesion, whereas soluble CXCL16 acts as a chemoattractant. 114 As CXCL16 was found to be highly expressed by OVA-expressing murine pancreatic cancer models and patient pancreatic ductal adenocarcinoma (PDAC) tumor biopsies, OT-I cells, murine EpCAM-targeting CAR-T cells, and human mesothelin-targeting CAR-T cells were transduced to express CXCR6. CXCR6-transduced EpCAM-targeting CAR-T cells induced significant tumor regression with complete tumor rejection in 40% of mice, which was superior to the regression observed with unmodified control, CXCR3-transduced, or CCR4-transduced EpCAM-targeting CAR-T cells.…”

CAR T Cell Immunotherapy Beyond Haematological Malignancy

“…Indeed, CCR8 and DNR-co-expressing CAR T cells showed even better efficacy against murine and human pancreatic cancers in mouse models. Similarly, Lesch et al ( 37 ) identified CXCL16 as an important chemokine secreted in murine pancreatic cancers, and their receptor CXCR6 was notably absent from cytotoxic T cells. Therefore, they engineered CAR T cells to co-express CXCR6 and demonstrated that these cells had both improved infiltration and killing of mouse subcutaneous pancreatic cancers, orthotopic pancreatic tumors, and patient-derived xenografts.…”

Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners

“…Tumor stroma serves as a physical tumor barrier, and the immunosuppressive microenvironment hinders CAR T cells from successfully infiltrating into the tumor site. Regional delivery [ 30 , 31 ] and co-expression of fibroblast activation protein (FAP) [ 32 ], heparanase enzyme [ 33 ], or specific chemokine receptors [ 34 , 35 , 36 , 37 ] on CAR T cells represent potential strategies to improve migration and infiltration. Additional strategies have been developed to shield CAR T cells from inhibitory signals of the tumor microenvironment such as the co-expression of a dominant-negative receptor (DNR) for transforming growth factor beta (TGF-β) [ 37 , 38 , 39 , 40 ].…”