Interactions between Tregs and antigen-presenting cells impair cytotoxic T-cell function in tumors.

  • Major finding: Interactions between Tregs and antigen-presenting cells impair cytotoxic T-cell function in tumors.

  • Mechanism: Treg-induced CD80 and CD86 depletion in APCs increases PD-1 and TIM-3 expression in cytotoxic T cells.

  • Impact: Treg-induced alterations in the balance of costimulatory and coinhibitory signals prevent tumor rejection.

Regulatory T cells (Treg) can suppress the activation of effector T cells and have been implicated in tumor immune tolerance, but the underlying mechanisms are not completely understood. To determine how antigen recognition affects immunomodulation by Tregs in tumors, Bauer and colleagues used a mouse model of adoptive T-cell therapy in which antigen-specific responses were evaluated by implanting transgenic tumor cells expressing an influenza antigen (HA) into wild-type mice at the same time as adoptive transfer of Tregs specific for HA (HA-Tregs), followed by HA-specific CD8+ (HA-CD8) CTLs 1 week later. HA-Tregs prevented tumor rejection by HA-CD8 CTLs, but if the tumor expressed a mutated HA not recognized by HA-Tregs, HA-Tregs no longer prevented tumor rejection, indicating a requirement for local antigen recognition by Tregs for tumor immune tolerance. HA-Tregs induced a hyporesponsive state in CTLs marked by low effector cytokine expression and inefficient cytotoxic granule release that resembled T-cell exhaustion. Consistent with these observations, HA-CD8s expressed higher levels of the coinhibitory receptors programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-3 (TIM-3) in the presence of HA-Tregs compared with non–HA-specific Tregs. Furthermore, dendritic cells (DC) pre-conditioned with HA-Tregs induced higher expression of PD-1 and TIM-3 in CTLs than DCs conditioned with HA antigen alone. Mechanistically, transient interactions between Tregs and antigen-presenting cells (APC) such as DCs in tumors led to reduced expression of the costimulatory factors CD80 and CD86, suggesting that Tregs dysregulate CTLs by simultaneously reducing costimulatory signals they receive from APCs and enhancing coinhibitory signals. Although the origin and antigen specificity of Tregs that reduce antitumor responses remains unknown, these data illustrate that antigen recognition by Tregs within tumors is required to impair CTL function and prevent tumor rejection.

Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest 2014;124:2425–40.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2014 American Association for Cancer Research.
2014