CD8+ T-cell memory in tumor immunology and immunotherapy

Abstract

The cellular and molecular mechanisms underlying the formation of distinct central, effector, and exhausted CD8+ T-cell memory subsets were first described in the setting of acute and chronic viral diseases. The role of these T-cell memory subsets are now being illuminated as relevant to the tumor-bearing state. The generation and persistence of productive CD8+ T-cell memory subsets is determined, in part, by antigen clearance, costimulation, responsiveness to homeostatic cytokines, and CD4+ T-helper cells. By contrast, chronic exposure to antigen, negative costimulation, and immunomodulation by CD4+ T regulatory cells corrupt productive CD8+ T memory formation. It has become clear from human and mouse studies that the mere generation of CD8+ T-cell memory is not a 'surrogate marker' for cancer vaccine efficacy. Some current cancer vaccine strategies may fail because they amplify, rather than correct or reset, the corrupted CD8+ memory population. Thus, much of the present effort in the development of vaccines for cancer and chronic infectious diseases is aimed at creating effective memory responses. Therapeutic vaccines for cancer and chronic infectious diseases may achieve consistent efficacy by ablation of the dysfunctional immune state and the provision of newly generated, non-corrupted memory cells by adoptive cell transfer.

Figure 1

Comparison of normal and corrupted CD8+ T-cell memory formation. CD8+ T-cell memory formation in the settings of an acute viral infection (A), chronic viral infection (B), and the tumor-bearing state (C) begins when a population of naive, antigen (Ag)-specific CD8+ T cells (blue cells) are stimulated to divide by exposure to cognate Ag. A productive encounter with cognate Ag induces a multi-log clonal expansion of this naïve precursor pool. As these cells divide, they acquire the phenotypic and functional attributes of terminally differentiated effector T cells (TEFF) (red cells) cells that allow these cells to clear the stimulating Ag. At the conclusion of the 1o response, the majority (∼90%) of responding CD8+ T cells die by apoptosis; a limited subset of TEFF cells (∼10%, green cells) advance to form a stable pool of memory CD8+ T cells. The memory pool is heterogeneous and can be divided into self-renewing central memory T cells (TCM) (aquamarine cells) and effector memory T cells (TEM) cells (yellow cells). Whether TEM convert to TCM with time is the current subject of controversy. Under normal conditions, both pools of memory T cells contribute to host protection from future pathogen challenge. In the settings of a chronic viral infection or the tumor-bearing state, the normal pattern of CD8 + memory T-cell production can be altered. With time, memory cells are driven to a highly differentiated or ‘exhausted’ phenotypic and functional state (purple cells), culminating in some cases in the deletion of responding cells. Ultimately, the memory CD8+ T cells generated under these conditions are unable to efficiently clear the challenging Ag, resulting in uncontrolled disease.

Figure 2

Phenotypic and functional changes in CD8+ T cells induced by chronic antigen stimulation. Chronic or repetitive antigen stimulation, such as that induced by chronic viral infections, the tumor-bearing state, and aggressive prime-boost regimens, drives naive CD8+ T cells to a terminally differentiated effector state (red cells) and ultimately to exhaustion (purple cells). The phenotypic changes characterizing this process are illustrated as low expression (+), intermediate expression (++), and high expression (+++) of various cell surface markers. Together with a shortening of the telomere length, CD8+ T cells progressively lose their proliferative potential and become exhausted and/or undergo apoptosis. In addition, CD8+ T cells lose the ability to secrete IL-2 and to respond to homeostatic cytokines such as IL-7 and IL-15. By contrast, effector functions and lytic capability are progressively gained with stimulation, peaking at the effector state but later becoming impaired in exhausted cells. Whether effector memory T cells (TEM) may revert to central memory T cells (TCM) following antigen clearance (not shown) is a current subject of controversy.