Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation

Our plain-English summary of Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation, by A.J. Currie, A. Prosser, A. McDonnell, et al (The Journal of Immunology, 2009).

The study

• Authors: A.J. Currie, A. Prosser, A. McDonnell, A.L. Cleaver, B.W. Robinson, G.J. Freeman, R.G. van der Most
• Journal: The Journal of Immunology
• Published: 2009;183(12):7898-908
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Tumors have evolved multiple mechanisms to evade immune destruction. One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1; B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. However, PD-L1 blockade only marginally affected tumor growth and was associated with the emergence of activated programmed death-1(+) ICOS(+) CD4 T cells in tumor-draining lymph nodes, whereas few activated CD8 T cells were present. Full activation of antitumor CD8 T cells, characterized as programmed death-1(+) ICOS(+) Ki-67(+) and displaying CTL activity, was only observed when CD4 T cells were depleted, suggesting that a population of suppressive CD4 T cells exists. ICOS(+) foxp3(+) regulatory T cells were found to be regulated through PD-L1, identifying one potentially suppressive CD4 T cell population. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies.

In plain English

In this laboratory study, the authors injected female BALB/c mice under the skin with AB1-HA mouse mesothelioma cells. The article describes this cell line as made from asbestos-induced mesothelioma cells and modified to carry an influenza virus protein as a model tumor antigen. No asbestos exposure was studied. The authors tested an antibody that blocks PD-L1, a molecule that can switch off immune T cells. They gave it alone or with CD4 T cell removal. PD-L1 was found on tumor cells and, at high levels, on dendritic cells in tumors. Blocking PD-L1 alone had a weak but statistically significant effect on tumor growth. It mainly activated CD4 T cells in lymph nodes draining the tumor. When CD4 T cells were also removed, blocking PD-L1 activated tumor-targeting CD8 T cells, which showed killing activity in all mice tested (3 per group); tumors also shrank. From day 28 tumors regrew, at the same time as CD4 T cells recovered. PD-L1 blockade also raised the share of foxp3 regulatory CD4 T cells. The authors concluded that PD-L1 blockade can unleash strong anti-tumor CD8 T cell responses, but only when suppressive CD4 T cells are absent.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mouse tumor model with antibody treatments)
• Who was studied: Female BALB/c mice aged 6 to 8 weeks, plus TCR-transgenic clone 4 mice, at the University of Western Australia. Groups in individual experiments were small: figure legends give 3 or 5 mice per group, from one experiment each. The symbol before each number is lost in the text.
• Exposure: Mice were given AB1-HA mesothelioma tumor cells under the skin of the flank. This line was made by adding the influenza virus HA gene, as a model tumor antigen, to asbestos-induced AB1 mouse mesothelioma cells. Mice were then treated with PD-L1 blocking antibody, CD4 T cell-depleting antibody (GK1.5), or both. No asbestos exposure was given in this study.
• Main results:
  • AB1-HA tumor cells grown in the laboratory expressed low levels of PD-L1. Within tumors, high-level PD-L1 expression was seen on CD11c-high dendritic cells.
  • PD-1 levels on CD8 T cells were variable, but overall significantly higher in lymph nodes draining the tumor than in non-draining nodes.
  • In mice with intact CD4 T cells, PD-L1 blockade alone had a weak but statistically significant effect on tumor growth. It induced activated PD-1-high ICOS-high CD4 T cells in tumor-draining lymph nodes, while CD8 T cells were not activated to a similar extent.
  • In CD4-depleted mice, PD-L1 blockade induced high frequencies of activated, proliferating (Ki-67-high) CD8 T cells. The authors reported up to 15% of all CD8 T cells in tumor-draining lymph nodes activated.
  • Untreated tumor-bearing mice showed little to no tumor-specific killing (CTL) activity in the body. CTL activity was somewhat increased with PD-L1 blockade alone, and higher but variable with CD4 depletion alone. It was high in all mice given the combination; the figure legend gives 3 mice per group.
  • Tumor regression was seen only with the combination of PD-L1 blockade and CD4 depletion; CD4 depletion alone led to tumor growth arrest. From day 28, tumors regrew, and in combination-treated mice they grew faster than in mice given only CD4-depleting antibody. The authors noted this coincided with CD4 T cell recovery.
  • PD-L1 blockade increased the frequency of foxp3 CD4 (regulatory) T cells in tumor-draining lymph nodes, and these cells expressed higher levels of ICOS.
• The authors' conclusion: The authors concluded that PD-L1 blockade can unleash strong anti-tumor CD8 T cell responses, but only when suppressive CD4 T cells are absent. They added that PD-L1 blockade may not always optimally activate anti-tumor CD8 T cell responses.
• Limitations the authors state:
  • The authors noted that the suppressive CD4 T cell population they identified may include cell types other than regulatory T cells. They based this on their earlier finding that removing CD25 cells alone did not affect tumor growth.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, Ki-67.

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