Tumor evasion from T cell surveillance

Abstract

An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells.

Figure 1

T-cell conversion from anergic to an activated status upon immunogenic cell death of tumor cells. The activation of tumor-specific T cells is dependent on DCs, which endocytose tumor cell debris and apoptotic vesicles. After intracellular processing the DCs present peptides derived from tumor-associated-antigens in complex with MHC class I molecules to T cells. Without the stimulation by danger-associated molecular patterns (DAMPs), DCs remain immature in a hostile immunosuppressive milieu and anergize CD4⁺ T cells and cytotoxic T cells (CTLs) resulting in peripheral tolerance. The release of inflammatory factors and the appearance of DAMPs lead to activation of DCs (inflammatory DCs) which subsequently upregulate costimulatory molecules of the B7 family. Inflammatory DCs are able to activate naïve CTLs through MHC I tumor peptide/TCR and B7/CD28 crosslinking. Furthermore, inflammatory DCs can activate naïve CD4⁺ T cells after MHC class II tumor peptide/TCR and B7/CD28 crosslinking. Activated CD4⁺ T cells in turn support clonal expansion and activity of CTLs by CD40/CD40L interaction and release of inflammatory cytokines such as IL-2.

Figure 2

Overview of immunosuppressive evasion mechanisms. Tumor cells and tumor-infiltrating Tregs and MDSC can employ a plethora of immunosupressive factors and molecules that impair T-cell function or lead to T-cell anergy and/or apoptosis. Depicted are immunosuppressive self-inhibitory circuits of activated CTLs and also immunosuppressive mechanisms of tumors.