Overcoming T cell exhaustion in infection and cancer

By Kristen E. Pauken, E. Wherry. Trends in immunology, 2015

1,080 citations recorded by the source corpus.

Inhibitors of the PD-1:PD-L1 pathway, a central regulator of T cell exhaustion, have been recently shown to be effective for treatment of different cancers. However, clinical responses are mixed, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Here we review the molecular regulation of T cell exhaustion, placing recent findings on PD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell exhaustion during chronic infection. We discuss the current understanding of the mechanisms involved in reversal T cell exhaustion, and outline critical areas of focus for future research, both basic and clinical.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/fc494e743314e2d9690f5ec7c705811bdf7c2259

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. E. Wherry
2. Rafi Ahmed
3. G. Freeman
4. Arlene H. Sharpe
5. V. Kuchroo
6. Laura M. McLane
7. K. Araki
8. A. Anderson

In Oncology

1. E. Wherry
2. Rafi Ahmed
3. Arlene H. Sharpe
4. G. Freeman
5. Laura M. McLane
6. V. Kuchroo
7. Mohamed S. Abdel-Hakeem
8. I. Mellman

Citations in the corpus

• Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent (2017, background): “Sustained expression of the inhibitory receptor PD-1 characterizes exhausted T cells, and PD-1 targeted therapies have shown clinical activity in a wide variety of cancer types (2, 3).”
• T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition (2016, background): “The interaction between PD-1 and its ligands also has been shown to restrain effector T cell activity against human cancers (10-14).”
• Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation (2016, background): “…in cancer (Callahan et al., 2016, this issue) and chronic viral infection (Attanasio and Wherry, 2016, this issue) where these receptors are highly expressed and are being targeted clinically to improve anti-tumor and anti-viral T cell responses (Mahoney et al., 2015; Pauken and Wherry, 2015).”
• Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “An additional hallmark of TEX is the expression of multiple inhibitory receptors, such as CTLA4, TIM3, LAG3, TIGIT, and others (Blackburn et al., 2009; Pauken and Wherry, 2015).”
• CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “It is also now clear that T cell exhaustion has a major role in immune dysfunction in cancer (22, 23).”