Features of responding T cells in cancer and chronic infection

Abstract

Ever since T cell exhaustion was initially characterized and thoroughly analyzed in the murine LCMV model, such a functional impairment has been validated in other chronic viral infections such as HIV, HCV, and HBV. In tumor immunology, it has always been postulated that tumor-reactive T cells could also become functionally exhausted owing to the high tumor-antigen load and accompanying inhibitory mechanisms. However, the empirical evidences for this hypothesis have not been as extensive as in chronic infection perhaps because much of the focus on T cell dysfunction in tumor immunology has been, and appropriately so, on breaking or bypassing immune tolerance and anergy to tumor/self antigens. On the basis of recent reports, it is becoming clear that T cell exhaustion also plays a crucial role in the impairment of antitumor immunity. In this review, we will comparatively evaluate the T cell responses in cancer and chronic infection, and the therapeutic strategies and interventions for both diseases.

Figure 1

Comparison of T cell dysfunction between chronic infection and cancer. In chronic infection, T cell dysfunction mainly occurs through functional exhaustion driven by high antigen load. In addition, there is an increased level of IL-10- and Treg-mediated immunosuppression of T cells. In cancer, functional exhaustion and immunosuppressive environment also negatively influence antitumor T cell responses, but there are additional factors that contribute to T cell dysfunction. Since most tumor antigens are endogenous, tumor-reactive T cells are inherently influenced by central and peripheral tolerance mechanisms. Anergy also plays a major part in T cell impairment in cancer. For example, tumor cells lack costimulatory molecules and are unable to provide the second signal to TILs during direct priming, and various antigen presenting cells in the tumor microenvironment have shown to induce T cell anergy.

Figure 2

Comparison of T cell dynamics between chronic infection and cancer. In chronic infection, antigen load primarily drives T cells to hierarchical exhaustion and ultimately deletion. In cancer, tumor/self-reactive T cells are initially kept in check by central and peripheral tolerance. Anergy is believed to occur immediately in tumor pathogenesis perhaps as early as in in situ cancer, whereas exhaustion/deletion most likely affects T cell function in more invasive cancer stages. One of the main purposes of tumor immunotherapy is to break immune tolerance and anergy. Treg depletion and CTLA-4 blockade can unleash tumor-reactive T cells for a potent antitumor response, but exhaustion/deletion may ultimately limit the treatment efficacy. Therefore, the therapeutic strategies used in chronic infection to rescue T cells from exhaustion, such as PD-1 or PD-1 plus LAG-3 blockade, also should be considered in tumor immunotherapy.