Trafficking of T Cells into Tumors

Abstract

T cells are a crucial component of the immune response to infection and cancer. In addition to coordinating immunity in lymphoid tissue, T cells play a vital role at the disease site, which relies on their efficient and specific trafficking capabilities. The process of T-cell trafficking is highly dynamic, involving a series of distinct processes, which include rolling, adhesion, extravasation, and chemotaxis. Trafficking of T cells to the tumor microenvironment is critical for the success of cancer immunotherapies such as adoptive cellular transfer. Although this approach has achieved some remarkable responses in patients with advanced melanoma and hematologic malignancy, the success against solid cancers has been more moderate. One of the major challenges for adoptive immunotherapy is to be able to effectively target a higher frequency of T cells to the tumor microenvironment, overcoming hurdles associated with immunosuppression and aberrant vasculature. This review summarizes recent advances in our understanding of T-cell migration in solid cancer and immunotherapy based on the adoptive transfer of natural or genetically engineered tumor-specific T cells and discusses new strategies that may enhance the trafficking of these cells, leading to effective eradication of solid cancer and metastases. Cancer Res; 74(24); 7168-74. Ó2014 AACR.

Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

“…77 This is particularly evident for gliomas, 78 colorectal, 79 breast 80 and cervical cancers. 81 An international consortium is currently prospectively validating this prognostic parameter as an 'immunoscore' for colorectal cancer.…”

Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors

“…In fact, improved antitumor responses have been shown to positively correlate with increased cytotoxic T lymphocyte (CTL) infiltration. CTL trafficking is a tightly controlled process, whose homing could be influenced by many factors, such as mismatching of chemokinechemokine receptor pairs, down-regulation of adhesion molecules, and aberrant vasculature (Slaney et al, 2014). CAR-T cell therapy is a personalized treatment involving genetic modification of autologous CTLs, enabling specific recognition and targeting of tumor-associated antigens expressed by the tumor cells or the tumor stroma.…”

“…Kandalaft et al demonstrated that blocking those receptors improved T cell infiltration into the tumor lesion and enhanced the efficacy of immunotherapy (Kandalaft et al, 2009). Another candidate for enhancing T cell infiltration is VEGF receptor-2, which is overexpressed by tumor-associated endothelial cells (Slaney et al, 2014). Throughout the history of cancer treatment, the long-term therapeutic effect of blocking VEGF receptor-2 has been a major anti-angiogenic pharmacologic intervention and has been fully dependent on CD8 + T cell infiltration in tumors (Manning et al, 2007).…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…stiffened tissue with high matrix fiber mass and dense collagen network) [113] or the low expression of specific chemokines involved in T-cell recruitment [13,31,114]. Often, the hindrance of lymphocyte infiltration and trafficking is accompanied by the recruitment of suppressive cells and may also be ascribed to abnormal neovasculature derived from VEGF tumor overexpression [21,115,116] and down-modulation by tumor cells of adhesion and chemotactic signals on tumor endothelium, all features found in signatures related to ICB resistance [21,30,117]. Furthermore, CCL2, a chemokine derived from stromal or tumor cells, chemoattracts macrophages and myeloid derived suppressor cells (MDSCs) [118,119], and is highly expressed in ICB-resistant melanoma [21].…”