Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication

Abstract

The continual interaction of the immune system with a developing tumor is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between effector and regulatory T-cell compartments. Whereas regulatory T cells can infiltrate and accumulate within tumors, effector T cells fail to efficiently do so. Furthermore, effector T cells that do infiltrate the tumor become tightly controlled by different regulatory cellular subsets and inhibitory molecules. The outcome of this balance is critical to survival, and whereas in some cases the equilibrium can rapidly result in the elimination of the transformed cells by the immune system, in many other cases the tumor manages to escape immune control. In this review, we discuss relevant work focusing on the establishment of the intratumor balance, the dynamic changes in the populations of effector and regulatory T cells within the tumor, and the role of the tumor vasculature and its activation state in the recruitment of different T-cell subsets. Finally, we also discuss work associated to the manipulation of the immune response to tumors and its impact on the infiltration, accumulation, and function of tumor-reactive lymphocytes within the tumor microenvironment.

Figure 1. The intra-tumor balance of effector and regulatory T cells

The infiltration of tumors by different subsets of lymphocytes can be initially affected by the activation state of the tumor vasculature as well as by the tumor microenvironment. During tumor progression and under non inflammatory conditions, a microenvironment rich on CCL22 and or CCL17 will favor recruitment of CD4⁺Foxp3⁺ T^reg cells via engagement of CCR4 on their cell surface. Furthermore, endothelin-1 produced by tumors will engage of ET_BR on the tumor endothelium and reduce infiltration by activated effector T cells through downregulation of ICAM on the tumor vasculature. Conversely, activation of the tumor vasculature by inflammatory mediators or by immunotherapy can increase the expression of adhesion molecules such as ICAM and VCAM thus favoring tumor infiltration by effector T cells. Once within the tumor, the balance is maintained by expansion and contraction of both regulatory and effector T cells. Low levels of co-stimulation, absence of Th1-type inflammation and presence of cytokines such as TGF-β may further contribute to conversion of CD4⁺Foxp3⁻ naïve or helper T cells into CD4⁺Foxp3⁺ regulatory T cells, thus tipping the balance towards tumor tolerance and escape. Although still on debate, changes in the stability of Foxp3 may result in regulatory T cells reverting into effector T cells. In addition, an increase on the levels of co-stimulatory molecules or inflammatory intermediates will also contribute to the accumulation of effector T cells and reduction of regulatory T cells within the tumor, consequently leaning the balance towards tumor elimination.