Enhancing Antitumor Immunity Targeting Regulatory T Cells

Published in Science Immunology, researchers led by Dario Vignali, PhD, distinguished professor and chair of the Department of Immunology and member of UPMC Hillman Cancer Center, identified a genetic mechanism to enhance an immune system’s antitumor activity. By finding a transcriptional network that regulates suppressive intratumoral regulatory T cells (Tregs), authors indicate that it may be possible to inhibit tumor-infiltrating lymphocyte Tregs (TIL Tregs) by targeting the distinct gene regulatory networks that control their suppressor function and activation without impairing the rest of the immune system.

Tregs regulate processes and suppress cells in the body that play a role in things like tissue repair, autoimmune diseases, or cancer. By controlling the immune response to both self and foreign particles, Tregs can help prevent and attack cancer. Furthermore, within a tumor, TIL Tregs exert immune suppressive functions that can make immunotherapy less effective. Therefore, inhibiting TIL Tregs to enhance antitumor immunity could be the key as long as homeostasis is not affected.

With the current methods of targeting Tregs for treatment, clinical researchers observed immune-related adverse effects in patients. The pathways that distinguish TIL Tregs from Tregs in healthy tissues remain largely unknown, so it is difficult to selectively target TIL Tregs while maintaining homeostasis and avoiding those adverse effects.

“Tregs are a subset of CD4+ T cells and they have phenotypic overlap with CD4+ effector T cells in the tumor microenvironment. CD4+ T effector cells can also temporarily express genes that used for identifying Tregs, which make it harder to target Tregs in the TME,” says first author Feng Shan, a graduate student in the Vignali Lab. “Additionally, Tregs are phenotypically and functionally heterogeneous within tumors, so we need additional markers to target those potent suppressive Tregs without affecting effector T cells and Tregs in non-malignant tissues.”

To find potential targets to modulate immunosuppressive Tregs and better maintain homeostasis, researchers sought to identify genes that are specific to TIL Tregs but not to other Tregs.

Using single-cell RNA sequencing, the team identified a subgroup of TNFR+ Tregs that is highly enriched in the tumor microenvironment compared to non-tumor tissue. TNFR+ Tregs are associated with worse prognosis in head and neck squamous cell carcinoma and other solid tumor types, suggesting that it suppresses antitumor immunity.

The authors found that the transcription factor BATF — a central component of a gene regulatory network governing TNFR+ Tregs — limits excessive activation and promotes the survival of human activated Tregs. They also identified surface molecules reflective of the BATF network, uncovering a primary regulator of highly suppressive intratumoral Tregs. The distinct population of suppressive intratumoral Tregs correlates with a poor prognosis across multiple solid tumors.

These findings highlight potential opportunities for therapeutic intervention in cancer targeting Tregs without impacting immune homeostasis — leading the way to more effective therapies.

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