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.

Trafficking of T Cells into Tumors

“…CD8 þ T cells are recruited from the circulation to the site of infection by a series of distinct processes, involving attachment/adhesion, rolling/tethering, chemotaxis, and extravasation (1,6). In general, T-cell trafficking to the tumor microenvironment is markedly reduced compared with an infectious disease setting due to both intrinsic and extrinsic factors (7). Despite this, immunotherapies using checkpoint inhibitors or adoptively transferred T cells have generated some remarkable responses against cancer particularly in patients with advanced metastatic melanoma (8)(9)(10).…”

“…1A, 2; ref. 7). The leakiness of the vessel can promote irregular blood flow causing inefficient trafficking of T cells within the tumor bed (7).…”

“…1A, 3). This phenomenon is called "EC anergy" and results in the inhibition of effector T-cell adherence to the EC and extravasation to the tumor site (7). Several strategies for normalizing tumor vasculature and inducing reexpression of adhesion molecules have been investigated (Fig.…”

“…1, box area). These include using antibodies targeting VEGF and its receptors that have been shown to transiently overcome EC anergy and enhance T-cell trafficking to the tumor site (7,23,24). In addition, other strategies for normalizing tumor vasculature include irradiation (25) or direct targeting of cytokines such as TNF to the blood vessel using tumor vasculature homing peptides NGR and RGR (7,26).…”

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

“…Another manifestation of tumor-promoted immune dysfunctions is the impairment in antigen presentation to T cells, which is essential for both endogenous and vaccine-induced activation of tumor-specific T cells (Gabrilovich, 2004;Herber et al, 2010;Yang et al, 2010). The metabolic adaptation of tumor cells generates a tumor microenvironment (TME) with pH and redox features that additionally contribute to limit T cell function and viability (Bellone and Calcinotto, 2013). These diverse mechanisms that we summarize in this review have limited the success of cancer immunotherapy and highlight the necessity for drugs that are able to modulate the immune dysfunctions associated with the TME.…”