T cell dysfunction in cancer: Anergy, Exhaustion, or Senescence?

Immune responses against cancer have been shown to be effective in eliminating tumors.  However anti-tumor immunity is limited by dysfunctional T cells which have been described in cancer patients.  Understanding how dysfunctional T cells arise in cancer and the potential mechanisms for restoring functionality are critical for developing effective immunotherapeutics.  In the current issue of Current Opinion in Immunology, Dr. Weiping Zou’s group, (Crespo. et. al.,) review the various types of T cell dysfunction that occur in the tumor microenvironment.

Anergy, exhaustion, and senescence are three different mechanisms underlying T cell hyporesponsiveness, which share distinguishing phenotypic features but arise by different mechanisms and under different experimental settings.  However, what is the difference between these three types of T cell dysfunction and which contribute to impaired T cell responses in the setting of cancer?

Anergy: T cell anergy generally refers to a hyporesponsive state in T cells induced by triggering the TCR either without adequate concomitant co-stimulation through CD28 or in the presence of high co-inhibitory molecule signaling.  Without both TCR and CD28 signals, IL-2 is not effectively transcribed and instead, anergy-associated genes such as GRAIL are expressed which contribute to impaired TCR signaling via negative feedback.

In the tumor microenvironment cancer, altered expression of B7 family members by APCs leads to an enhanced expression of B7 family co-inhibitory molecules including PD-L1 and a reduction in the B7 family co-stimulatory molecules CD80 and CD86.  Thus, T cell activation in this environment could lead to induction of anergy.

Exhaustion: T cell exhaustion occurs as a result of chronic over-stimulation, such as occurs in the settings of chronic viral infections including hepatitis C virus (HCV) and HIV, autoimmunity, and cancer.  Exhausted T cells progressively lose the ability to express effector cytokines including IL-2, IFNg, and TNFα.  They also express multiple inhibitory receptors including PD-1 and LAG-3, lose cytotoxic and proliferative potential, and may ultimately be driven to apoptosis.

Because anti-tumor T cells are persistently exposed to antigen in the tumor microenvironment, exhaustion is a likely mechanism contributing to T cell dysfunction in cancer patients.  As such, exhausted T cells have been described in patients with melanoma, ovarian cancer and hepatocellular carcinoma.

Senescence:  Senescence is thought to occur due to the natural life span, or aging of cells.  However, senescent T cells have been observed in the settings of chronic inflammation and persistent infection in young individuals, indicating other factors beyond a person’s age, such as DNA damage, drive acquisition of this state.  Senescent T cells are marked by deficient CD28 expression, telomere shortening, expression of regulatory receptors such as TIM-3 and KLRG-1, and inability to progress through the cell cycle.

Cells with features of senescence have been described in patients with lung cancer, head and neck cancer, hepatocellular carcinoma, melanoma and lymphoma.  Thus, senescence may also contribute to T cell dysfunction in cancer patients.

In conclusion, there is evidence that anergy, exhaustion, and senescence may all be contributing toward T cell dysfunction in cancer.  In the review, Crespo. et. al., make the point that distinguishing cells in these states may be complicated as they overlap phenotypically and in expression of various markers.  Furthermore, the mechanisms mediating establishment of these three states is not well defined.  However, it is important to clarify the mechanisms by which T cells gain and maintain dysfunction in cancer in order to best develop effective immunotherapeutics.


Further Reading:

 T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment.  Crespo J, Sun H, Welling TH, Tian Z, Zou W.  Curr Opin Immunol. 2013 Jan 5.

The three main stumbling blocks for anticancer T cells.  Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. Trends Immunol. 2012 Jul;33(7):364-72.

Induction of T cell anergy: integration of environmental cues and infectious tolerance. P. Chappert, R.H. Schwartz.  Curr. Opin. Immunol., 22 (2010), pp. 552–559.

T cell exhaustion.  E.J. Wherry.  Nat Immunol, 12 (2011), pp. 492–499.

T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection.  A.N. Vallejo, C.M. Weyand, J.J. Goronzy.  Trends Mol Med, 10 (2004), pp. 119–124.