A STAT5 activator protects CD8+ T cells in immunosuppressive environments

• Published in: The Journal of immunology (1950) Vol. 210; no. 1_Supplement; pp. 154 - 154.17
• Main Authors: Shudde, Claire E, Gu, Zehui, Piper, Taylor L, Zheng, Yating, Courtney, Adam H
• Format: Journal Article
• Language: English
• Published: 01-05-2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.154.17

Abstract
CD8+ T cells are central mediators of an anti-tumor immune response because they can recognize and kill cancerous cells. However, cancer can evade this attack by establishing a tumor microenvironment (TME) that suppresses CD8+ T cells by depriving them of pro-survival cytokines, such as IL-2. IL-2 has been directly administered to cancer patients as an immunotherapy, but was found to cause broad immune activation that could result in multi-organ failure and possessed poor pharmacologic properties. To address these limitations, we have devised a strategy to activate the intracellular mediator of IL-2 signaling – STAT5. The activator of endogenous STAT5 that we developed was evaluated for its capacity to maintain T cell survival and function. To recapitulate a niche devoid of pro-survival cytokines like the TME, we activated CD8+ T cells in the absence of IL-2 and evaluated their viability in culture. We determined that direct activation of STAT5 could maintain CD8+ T cell viability up to 10 days post-activation, whereas control cells died off by day 3. To investigate whether STAT5 activation could be used to retain CD8+ T cell function, we assessed the potential of these cells to become activated by antigen and kill cancerous cells. We found that T cells that persisted in the absence of IL-2 due to STAT5 activation could upregulate a reporter of T cell activation (Nur77-GFP) and kill cancer cells ex vivo. Moreover, STAT5 activation enabled CD8+ T cells to produce IFNγ upon restimulation by antigen presenting cells. Our data demonstrate that a STAT5 activator can be used to maintain T cell survival, activation, and cytotoxic capacity in cytokine-depleted environments, suggesting its potential to counteract an immunosuppressive TME.
Supported by grants from NIH (T32GM140223), V Foundation for Cancer Research, and the Concern Foundation