T-cell Dysfunction in Glioblastoma: Applying a New Framework

Abstract

A functional, replete T-cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive antitumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging antitumor immunity, eliciting severe T-cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anticancer immune-based therapies. Although T-cell dysfunction in GBM has been long described, newer immunologic frameworks now exist for reclassifying T-cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T-cell deficits elicited by GBM within the context of the five relevant categories: senescence, tolerance, anergy, exhaustion, and ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T-cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them. Clin Cancer Res; 24(16); 3792-802. ©2018 AACR.

Figure 1. Senescence

A, T-cell senescence results from telomere shortening as a result of T-cell proliferation/activation or through DNA damage, for example, exposure to reactive oxygen species (ROS). CD57 serves as a marker for senescent T cells. B, Thymic involution, or thymic shrinkage, occurs with age and is prominent in GBM, as evidenced by reduced recent thymic emigrants (RTE) and T-cell receptor excision circles (TREC). Redrawn from an illustration by Megan Llewellyn, MSMI; copyright Duke University with permission under a CC-BY 4.0 license.

Figure 2. Tolerance

A, Peripheral deletion is a form of peripheral tolerance. Peripheral deletion in GBM is accomplished through FasL-mediated apoptosis. B, Regulatory T cells (Treg) induce immunosuppressive effects both peripherally and at the tumor site in GBM. STAT3 and IDO both modulate Treg function, resulting in further immunosuppression. Redrawn from an illustration by Megan Llewellyn, MSMI; copyright Duke University (Durham, NC) with permission under a CC-BY 4.0 license. Teff, effector T cell.

Figure 3. Anergy

A, Historically, anergy described the lack of delayed-type hypersensitivity (DTH) responses when patients with GBM failed to react to recall antigens. B, Clonal or in vitro anergy describes a mostly unresponsive state elicited by insufficient costimulation resulting in defective RAS/MAPK activation. Defective RAS/MAPK activation results in decreased AP-1 transcription, preventing T-cell activation. C, Adaptive tolerance or in vivo anergy results from continuous low levels of antigen exposure, leading to impairments in IL2 production and T-cell proliferation through deficits in Zap70 kinase activity. Defective Zap70 activation results in impaired mobilization of calcium and NF-κB. Redrawn from an illustration by Megan Llewellyn, MSMI; copyright Duke University (Durham, NC) with permission under a CC-BY 4.0 license. NFAT, nuclear factor of activated T cells.

Figure 4. Exhaustion

Physiologic coupling of NFAT and AP-1 results in expression of activating genes (i.e., IL2). In the course of chronic antigen exposure, failure of NFAT to form a complex with AP-1 leads to expression of inhibitory checkpoints. Redrawn from an illustration by Megan Llewellyn, MSMI; copyright Duke University (Durham, NC) with permission under a CC-BY 4.0 license.

Figure 5. Ignorance

A, The brain has long been characterized as immunologically “privileged,” with limited ability of the immune system to infiltrate. Today, the brain is recognized as “immunologically distinct,” where immune cells can and do infiltrate, yet the microenvironment may result in unique forms of immunosuppression. B, Clinically significant lymphopenia in patients with GBM, in part due to bone marrow T-cell sequestration as a result of S1P1 loss. Redrawn from an illustration by Megan Llewellyn, MSMI; copyright Duke University (Durham, NC) with permission under a CC-BY 4.0 license.