Enhancement of T cell recruitment and infiltration into tumours

Abstract

Studies have documented that cancer patients with tumours which are highly infiltrated with cytotoxic T lymphocytes show enhanced survival rates. The ultimate goal of cancer immunotherapy is to elicit high-avidity tumour-specific T cells to migrate and kill malignant tumours. Novel antibody therapies such as ipilumimab (a cytotoxic T lymphocyte antigen-4 blocking antibody) show enhanced T cell infiltration into the tumour tissue and increased survival. More conventional therapies such as chemotherapy or anti-angiogenic therapy and recent therapies with oncolytic viruses have been shown to alter the tumour microenvironment and thereby lead to enhanced T cell infiltration. Understanding the mechanisms involved in the migration of high-avidity tumour-specific T cells into tumours will support and provide solutions for the optimization of therapeutic options in cancer immunotherapy.

Keywords: T cells; cancer; tumour immunology.

Fig 1

Strategies to enhance T cell infiltration into tumour tissue. (a) Tumours secreting vascular endothelial growth factor (VEGF) leads to an abnormal blood vessel formation and decreased T cell infiltration. Anti-VEGF antibody and BRAF inhibitors decrease VEGF and normalize blood vessel formation; (b) treatment with paclitaxel and thalidomide also leads to blood vessel normalization and increased T cell infiltration; (c) anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies increase T cell infiltration into tumours and decrease regulatory T cells (T_regs); (d) up-regulation of chemokine ligand (CCL)17 and CCL22 leads to T_reg accumulation within the tumours; cyclophosphamide treatment has been associated with decreased T_reg cell infiltration; suppression of T_regs in the tumour microenvironment can increase the expression of adhesion molecules (VCAM-I and ICAM-I), leading to enhanced T cell infiltration; (e) down-regulation of chemokines in the tumour environment has been associated with decreased T cell infiltration; (f) expression of CXC chemokine ligand (CXCL)16 and CXCL12 enhance T cell infiltration to the tumour site; (g) anti-PD-L1 therapy has been shown to enhance interferon (IFN)-gamma and CXCL10 expression leading to T cell infiltration; (h) oncolytic virus therapy encoding Toll-like receptor (TLR) can enhance T cell infiltration through up-regulated expression of TLR on tumour cells.