Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes

Abstract

The tumor is a hostile microenvironment for T lymphocytes. Indeed, irregular blood flow, and endothelial cell (EC) anergy that characterize most solid tumors hamper leukocyte adhesion, extravasation, and infiltration. In addition, hypoxia and reprograming of energy metabolism within cancer cells transform the tumor mass in a harsh environment that limits survival and effector functions of T cells, regardless of being induced in vivo by vaccination or adoptively transferred. In this review, we will summarize on recent advances in our understanding of the characteristics of tumor-associated neo-angiogenic vessels as well as of the tumor metabolism that may impact on T cell trafficking and fitness of tumor infiltrating lymphocytes. In particular, we will focus on how advances in knowledge of the characteristics of tumor ECs have enabled identifying strategies to normalize the tumor-vasculature and/or overcome EC anergy, thus increasing leukocyte-vessel wall interactions and lymphocyte infiltration in tumors. We will also focus on drugs acting on cells and their released molecules to transiently render the tumor microenvironment more suitable for tumor infiltrating T lymphocytes, thus increasing the therapeutic effectiveness of both active and adoptive immunotherapies.

Keywords: NGR-TNF; adoptive T cell therapy; combination therapy; cytotoxic T lymphocyte; pH; proton pump inhibitor; redox; vaccine.

Figure 1

Strategies that favor lymphocyte trafficking into tumors and fitness of TILs. The cartoon highlights abnormalities of tumor-associated vessels and alterations of the metabolism within the tumor microenvironment that limit lymphocyte trafficking into tumor and TIL anti-tumor activities. Strategies to overcome such hurdles are also indicated.

Figure 2

Strategies to increase T cell infiltration into tumors. (A) Increased interstitial pressure, heterogeneous permeability and irregular blood flow, together with reduced expression of adhesion molecules on ECs, limit lymphocyte penetration in tumors. (B) NGR-TNF, which selectively binds CD13 expressed in ECs of neo-angiogenic vessels and favors the interaction of TNF with TNF receptors (TNF-Rs), alters tumor vessel permeability by loosening VE-cadherin dependent adherence junctions, induces up-regulation of adhesion molecules in ECs, and elicits the release of pro-inflammatory cytokines and chemokines, thereby favoring the recruitment and extravasation of T lymphocytes. (C) Anti-VEGF and anti-VEGF-R antibodies both transiently normalize the tumor-vasculature and overcome EC anergy, thus favoring T cell trafficking within tumors. (D) Also immunization against VEGF-R2 or the adoptive transfer of autologous T cells genetically engineered to express chimeric antigen receptor targeted against VEGF-R2 (VEGFR-CAR) favor tumor infiltration by T cells, although the mechanism has not yet been clarified. It has been proposed that VEGF-R-specific T cells kill both ECs and MDSCs and Tregs (not shown) that express VEGF-R.

Figure 3

Metabolic alterations within the tumor microenvironment. The cartoon summarizes the metabolic alterations often found within the tumor microenvironment that may impact on T cell fitness. See the text for more details. ATP, Adenosine-5′-triphosphate; HIF-1, hypoxia inducible factor 1; ROS, reactive oxygen species; TRX, thioredoxin.