Tumor microenvironment and lymphocyte infiltration

Abstract

There is ample evidence that the presence of tumor-infiltrating T lymphocytes is associated with a favorable prognostic in patients. These observations suggest that a limiting step to immune resistance and immunotherapy could be the capacity of tumor-specific T cells to reach tumor bed. In this article, we review some factors that may influence this infiltration, and in particular the nature of the vasculature, the expression of chemokines or tumor antigens and the presence of dendritic cells and CD4+ T lymphocytes.

Fig. 1

Schematic representation of tumor infiltration. Tumor clinical outcome is often associated with the presence of tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures and/or high endothelial venules (HEVs). However, during tumor progression, tumor vessels may become heterogenous and tortuous, which could result from (1) production by tumor and/or myeloid cells (MC) of VEGF which induces abnormal differentiation and proliferation of endothelial cells and is a negative regulator of pericyte function [21, 22]; (2) secretion of endothelin-1 (ET-1) by tumor cells, which upon interaction with its ligand (ET_BR) expressed by tumor abnormal vessels, inhibits T cell adhesion to endothelium by NO production and downregulation of ICAM-1 molecules [24]. EC endothelial cells, VEGF vascular endothelial growth factor, VEGFR-P VEGF receptor phosphorylated

Fig. 2

Potential roles of CD4⁺ T lymphocytes in chemokine production involved in the recruitment of tumor-specific CD8⁺ T lymphocytes. In several tumors in mice and humans, Th1 cells have been shown to produce IFN-γ which induces the expression of CXCL9 and CXCL10 in the tumor microenvironment. Similarly, in one pancreatic tumor model, CCL3 and CCL5 are induced by CD4⁺ T cells producing IFN-γ [48]. The role of Th17 cells is less clear: they may act as inducers of the expression of CCL2 and CCL20 in the tumor environment to recruit CD8⁺ T lymphocytes [51] and/or as activators of Th1 cells to produce IFN-γ and CXCL9/CXCL10 chemokines required for CD8⁺ T cell migration [52]