Cell: Tumor immunotherapy will self-limit its efficacy, by activating Treg cells, reducing the effect of immunotherapy

As tumor immunotherapy has gradually become one of the important directions of clinical targeted drug research and development, more and more tumor immunotherapy gene targets have entered the field of research and development

In addition to PD-1 / PD-L1, CTLA-4 is also a popular tumor immunotherapy target

CTLA-4, or cytotoxic T lymphocyte-associated protein 4, is a leukocyte differentiation antigen and a transmembrane receptor on T cells, which acts as an immune checkpoint and down-regulates the immune response

However, immune checkpoints are only one component of the multi-level regulatory mechanism system

Recently, the research team at Harvard Medical School in top international academic journal Cell published a report entitled: Expansion of tumor-Associated Treg cells upon disruption of CTLA-4-dependent A Feedback Loop research papers

The study used in vivo imaging technology to find that anti-cancer drugs inhibit CTLA-4 molecules and activate CD8 and CD4 effector T cells, thereby killing cancer

In order to examine the single-cell dynamics of Treg cell activation in tumor tissues through in vivo imaging, the research team infected Treg cells with a retrovirus expressing NFAT-GFP and the fluorescent histone fusion protein H2B-RFP and implanted them under the skin of mice

The results show that, unlike traditional helper Th cells, these Treg cells are activated during stable antigen contact, indicating that the Treg cell bank is pre-enriched in TME to recognize the antigen, while only rare cells in the Th cell bank recognize Antigen

In addition, although Treg cells only partially stabilized their interaction with antigen-presenting cells (APC) in tumor tissues, these unstable interactions trigger the T cell antigen receptor (TCR) signal that activates the NFAT pathway

Because conventional dendritic cells (cDC) help recruit and activate tumor-infiltrating cytotoxic T lymphocytes (CTL), the research team hypothesized that they may also activate Treg cells

Considering that the TCR sequences of tumor infiltrating Th and Treg cells are largely different, Treg cells will destroy the contact between APC and Th cells in the tumor

The results suggest that the difference in the interaction between Treg and Th cells and APC is not driven by the inherent difference in TCR affinity, but by the change in TME introduced by Treg cells

So, how do Treg cells affect the stability of Th cells and their interaction with tumor-associated APCs?

Because Treg cells can use CTLA-4 that costimulates B7 family proteins to reduce the number of CD80 and CD86 on APC in SLO, and considering the high expression of CTLA-4 on tumor-infiltrating Treg cells, the research team explored the regulation of CTLA-4 The function of the stability of the interaction between T cells and APC in tumor tissues

They found that CTLA-4 restricted the expression of CD80 and CD86 on tumor-infiltrating cDCs, restricted the proliferation of local Treg cells, and required concomitant Treg cell inactivation to achieve tumor rejection

Therefore, Treg cells self-regulate through a feedback loop that relies on CTLA-4 and CD28, which adjusts their population size based on the amount of local co-stimulation

In summary, this study confirmed in preclinical tumor models that Treg cells express costimulatory proteins CD80 and CD86 on conventional dendritic cells (cDC)

Original source:

Francesco Marangoni, et al.
Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop.
Cell, 2021.
DOI: https://doi.
org/10.
1016/j.
cell.
2021.
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