Antigen-Specific inhibition of High Avidity T Cell Target Lysis by Low Avidity via Trogocytosis.

In this report, we demonstrated that anti-tumor activity of high-avidity T cells can still be inhibited by low-avidity T cells in an antigen-specific manner in vitro and in vivo. This inhibition occurs through a trogocytosis mechanism in which low-avidity T cells strip cognate peptide-MHCs from the target cell surface without killing, leaving subthreshold levels of target peptides accessible to high-avidity T cells. Antigen-specific inhibition of high-avidity T cells by low-avidity T cells represents a mechanism of immune regulation (Cell Rep. 2014;8(3):871-82).

 

Engineering the Human Thymic Microenvironment to Support Thymopoiesis in Vivo.

Here, we demonstrated that the human 3D-thymic aggregate system can thus be used to study the recruitment of human hematopoietic stem cells from bone marrow to the thymus, and subsequent in vivo differentiation of T cells. The scale‐up of this approach would also offer a potentially clinically relevant method for transplantation of T cell depleted postnatal thymus. Moreover, we provide proof‐of‐principle that signals from the thymic microenvironment can be engineered with this method, opening up potential applications for the control of T cell growth, differentiation and function within the thymus (Stem Cells. 2014;32(9):2386-96 ).

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Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12.

Our studies showed that metastatic cancer associated fibroblasts (CAFs) from brain metastases produce high levels of chemokines CXCL12 and CXCL16, promoting the migration of patient-specific breast cancer cells in a 3-D aggregate system. Moreover, blocking of CXCR4, the chemokine receptor for CXCL12, and neutralization of CXCL16, the ligand for CXCR6 in patient-specific cancer cells significantly prevented the migration of cancer cells to the tumor microenvironment (TME). These novel findings from our 3D CAF aggregate system provide proof of principle that chemokine modulation represents an effective therapeutic strategy to prevent tumor progression and metastasis (npj Breast Cancer (2017) 3:6).

 

The use of EGFR-CD3 bispecific antibody and antigen-specific high avidity CTL to target cancer associated fibroblasts and cancer cells within a melanoma organoid model system. 

In this report, we demonstrated that upon exposing the 3D aggregate to the high-avidity CD8 CTLs and BiAbs, the melanoma specific T cells were induced to also target EGFR expressing CAFs. The BiAb mediated destruction of these CAFs allowed the high avidity T cells to penetrate the surrounding layer of CAFs and perform their endogenous cytotoxic activity on the cancer cells within. These findings provide proof of concept that targeting the CAFs through BiAbs concurrently with tumor cells may be an effective method to enhance current T cell based immunotherapies (under revision. 2017).

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