Tregs and rethinking cancer immunotherapy

Abstract

Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm.

Figure 1. The not enough of a good thing paradigm.

APCs (especially DCs) capture antigen from tumor cells. Antigen-loaded APCs then prime naive T cells to become antitumor CTLs through soluble mediators such as IL-12 and/or cosignaling molecules such as CD80 or CD86. Failure to elicit protective immunity is seen as a lack of sufficient quantity or quality of 1 of these events (indicated in red text). This model predicts that augmenting numbers or quality of a specific component will suffice as a clinical strategy.

Figure 2. Natural and adaptive Tregs.

(A) Natural Tregs arise in the thymus under homeostatic conditions, through the integration of a myriad of local thymic factors. Thymically derived natural Tregs defend against autoimmunity. (B) Adaptive Tregs arise in the periphery (outside the thymus), either from natural Tregs receiving additional signals or through an independent pathway. Both natural and adaptive Tregs might contribute to tumor immunopathology. CTLA4, cytotoxic T lymphocyte–associated antigen 4.

Figure 3. The too much of a bad thing paradigm.

Dysfunctional APCs, aberrant cosignaling, and other factors (such as prostaglandins, counterregulatory cytokines, and hypoxia) help generate Tregs and other mediators of immune pathology. These pathways, and the products and cells that they generate, must be defeated for optimal tumor immunotherapy.