NOV 14, 2018 8:02 PM PST

Reversing T Cell dysfunction in Cancer: Getting the Body to Fight its own Battles

Using the power of the immune system to eliminate cancerous cells has long the been the goal of immuno-oncology. Immune cells naturally recognize, destroy, and remember the abnormal cells within our bodies while also overlooking healthy cells. This process is called self-tolerance, and when working well, allows the body to rid itself of abnormalities without collateral damage. The challenge with cancer is that tumors can co-opt a variety of self-tolerance mechanisms to evade the destructive potential of the immune system.

Cytotoxic T cells (red) attacking an oral squamous cancer cell (white) by Rita Elena Serda

Self tolerance prevents the immune system from becoming overactive and protects against autoimmunity. Autoreactive immune cells are either destroyed or left inactive. For example, circulating T cells are prevented from excessive proliferation and cytotoxicity by signaling molecules expressed on tissue and regulatory T cells with suppressive functions called Tregs. Tumors take advantage of this self tolerance in order to grow unchecked. A comprehensive approach to reversing this dysfunction by (1) activating cancer-specific cytotoxic T cells, (2) releasing T reg suppression, and (3) producing tumor-specific memory T cells has been termed the immune checkpoint blockade.

Current attempts to achieve the immune checkpoint blockade have focused on targeting signaling molecules involved in maintaining self tolerance. Two such proteins are PD-1 and GITR, and both are frequently exploited by tumors. PD-1 is a protein that acts as a “brake” for the immune system. It is expressed on immune cells including T cells and T regs. Its ligand is expressed on both healthy tissue and tumors. PD-1 signaling inhibits the activity of cytotoxic T cells while promoting the expansion of Tregs.

GITR is a cell surface receptor that acts as an “accelerator” for the immune system. Like PD-1, GITR is found on activated T cells and Tregs, but it has the opposite function. GITR signaling promotes cytotoxic T cell expansion and inhibits Treg activity.

Initially, scientists attempted to activate anti-tumor immunity by either inhibiting PD-1 signaling (cutting the “brakes”) or activating GITR signaling (revving the “accelerator”). Neither indvidual approach was able to achieve immune checkpoint blockade. However, a combinatorial method using an antibody to block PD-1 signaling (anti-PD-1) while simultaneously activating GITR signaling by antibody (anti-GITR) has shown promise.

“In preclinical studies in which monotherapy with anti-GITR or anti–PD-1 Ab has limited efficacy… combination therapy was able to achieve long-term survival in mouse models of ovarian and breast cancer”

To study this anti-tumor treatment, Bei Wang and others at Regeneron Pharmaceuticals used a murine colon adenocarcinoma model to analyze populations of intratumoral cytotoxic CD8+ T cells and Tregs following treatment with anti-PD-1 and/or anti-GITR antibodies. Monotherapy with either anti-PD-1 or anti-GITR were not capable of controlling tumor growth as neither could overcome the immune checkpoint. However, the combination therapy resulted in the rejection of the tumors along with in an increased ratio of T cells to Tregs. Further studies showed that tumor rejection was CD8+ T cell dependent, cancer specific, and that the CD8+ T cells contained memory cell precursors suggesting anti-tumor memory.

The higher numbers of functional CD8+ T cells compared to Tregs along with the rejection of the tumors and presence of memory cell precursors after the combination treatment suggests that the immune checkpoint blockade was successful. Excitingly, this therapy does not appear to be cancer type specific as anti-PD-1 + anti-GITR treatment also resulted in rejection of a mouse model of kidney carcinoma.


It will be interesting to see whether this combination treatment, with or without cancer vaccination or chemotherapy, has the same dramatic results in humans.

Sources: European Journal of CancerScience ImmunologyJohns Hopkins Medicine;

About the Author
  • Aleishia is a freelance medical/science writer that specializes in research-oriented content. Contact her for work.
You May Also Like
AUG 30, 2021
Cancer
A Hot Approach to CAR T Cells
AUG 30, 2021
A Hot Approach to CAR T Cells
Immunotherapy, a type of treatment that targets a patient’s immune system to enhance the natural ability to attack ...
SEP 02, 2021
Immunology
Will an Extra COVID Vaccine Shot Benefit People With Autoimmune Conditions?
SEP 02, 2021
Will an Extra COVID Vaccine Shot Benefit People With Autoimmune Conditions?
The global rollout of COVID-19 vaccines has helped save countless lives during the pandemic. Studies have shown that vac ...
SEP 03, 2021
Cell & Molecular Biology
Is a Venom-Like Molecule Involved in COVID-19 Mortality?
SEP 03, 2021
Is a Venom-Like Molecule Involved in COVID-19 Mortality?
Scientists have sought to learn more about why some people get severe COVID-19 while others have only mild cases. We kno ...
SEP 07, 2021
Immunology
Designer Cells for Treating Arthritis Are Activated by Inflammation
SEP 07, 2021
Designer Cells for Treating Arthritis Are Activated by Inflammation
Scientists have developed a new cell therapy for arthritis that becomes activated in the presence of inflammation. When ...
SEP 14, 2021
Immunology
The Spleen Creates Long-Lasting Protection Against the Flu Virus
SEP 14, 2021
The Spleen Creates Long-Lasting Protection Against the Flu Virus
You share an elevator with an individual who is coughing and sneezing, only to find yourself feeling unwell a few days l ...
NOV 01, 2021
Cell & Molecular Biology
How SARS-CoV-2 Evades Antiviral Defenses
NOV 01, 2021
How SARS-CoV-2 Evades Antiviral Defenses
Researchers have learned a lot about the SARS-CoV-2 virus since the start of the COVID-19 pandemic. We know that he viru ...
Loading Comments...