The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

Abstract

Analysis of tumor infiltration using conventional methods reveals a snapshot view of lymphocyte interactions with the tumor environment. However, lymphocytes have the unique capacity for continued recirculation, exploring varied tissues for the presence of cognate antigens according to inflammatory triggers and chemokine gradients. We discuss the role of the inflammatory and cellular makeup of the tumor environment, as well as antigen expressed by cancer cells or cross-presented by stromal antigen presenting cells, on recirculation kinetics of T cells. We aim to discuss how current cancer therapies may manipulate lymphocyte recirculation versus retention to impact lymphocyte exclusion in the tumor.

Keywords: T cell; clonality analysis; recirculation; recruitment; retention; tumor.

Figure 1

Dynamic view of cell infiltration in tumors. (A) A highly infiltrated tumor may also represent a high rate of throughput of immune cells. i) a static view shows large numbers of T cells in the tumor. ii) a dynamic view shows a high rate of surveillance and recirculation. Iii) a dynamic view of a poorly infiltrated tumor shows a low rate of surveillance and recirculation. Understanding the kinetic will help understand the rate of accrual versus accumulation in the environment. (B) Change in lymphocytes in tumors over time with unchanged overall infiltration. i) Lymphocytes present at baseline are green. ii) Those newly present at the second timepoint are red, and iii) newly present at the third timepoint are yellow. At each timepoint not all cells are replaced, and those exhibiting prolonged interactions in the tumor are more likely to have engaged their cognate antigen.

Figure 2

Change in lymphocytes in tumors due to increase infiltration versus increased retention. (A) Effect of increasing lymphocyte infiltration via chemokines and inflammatory changes in the tumor vasculature on T cell diversity in the tumor. Lymphocytes present at baseline are green. Those newly present at the second timepoint are red. (B) As with (A), but the effect of increasing T cell retention via increased antigen-specific interactions via altered antigen presentation or costimulation. (C) Higher expression of chemokines that can attract activated T cells in cancer cells will cause proportional enrichment of immune cells in the vicinity of cancer cell nests. By contrast higher expression of the same chemokines in the tumor stroma may cause their enrichment in the stroma but exclusion from the cancer cell nests, limiting their cytotoxic potential.

Figure 3

Impact of the tumor stroma and the stromal traverse on T cell dynamics. (A) The tumor is a non-homogenous structure that can be generally split into tumor and stroma. A diverse population of immune cells enrich in stroma away from direct cancer cell contact, and closer to vascular points of entry and lymphovascular points of exit. Different tumors can vary widely in the extent of tumor stroma. capacity for direct cancer cell cytotoxicity. (B) Following entry of lymphocytes into the tumor stroma via the vasculature, there are multiple stromal barriers that can cause T cell arrest and provide opportunities for a dominance of exit signals for continued recirculation through efferent lymphovasculature, rather than continuing through the stroma to meet cancer cells. More extensive stroma may increase the duration of traverse and decrease the likelihood of T cells meeting cancer cells.

Figure 4

Varying thresholds for T cell function according to extent of TCR-MHC interactions. As the extent of cognate antigen increases on a target, whether by improved antigen expression or increased antigen processing and presentation, the intensity of T cell recognition allows the T cell to pass through various thresholds of response. The position of these thresholds can be altered by checkpoint blockade or costimulatory agonists. T cells in established tumors are typified by phenotypic modification without successful cytotoxic elimination of the cancer cells.