Do Tregs link sepsis to tumor growth?

Sepsis has been shown to induce an immune suppressive state that includes the expansion of CD25⁺CD4⁺ FoxP3⁺ T regulatory cells (Tregs). In this issue of Blood, Cavassani and colleagues demonstrate that Treg expansion in the postseptic period contributes to increased tumor growth.

The immune suppressive state associated with severe sepsis is easily recognized, but still remains poorly described. The late Roger Bone coined the term, the “compensatory anti-inflammatory response syndrome (CARS)” to reflect what he proposed was a reactive response to an exaggerated early innate immune activation and inflammation.¹  Bone also coined “immunoparalysis,” which refers to the postsepsis response that is thought to not only impair resolution of the initial infection, but also to predispose the septic patient to secondary nosocomial infections.^1,2  In this issue of Blood, Cavassani et al provide evocative data suggesting that sepsis and its associated alterations in immune function may not only reduce immune surveillance but also contribute to more rapid growth of established solid tumors.³  Although there are a plethora of immunosuppressive mechanisms that have been described during the postsepsis period, the authors focus their investigation on regulatory T-cell populations (Tregs).

Is this a reasonable suggestion? Sepsis-induced immune suppression is clearly multifactoral, but there is increasing evidence that sepsis is associated with the expansion of several suppressor cell populations, including both Tregs and the more newly described myeloid derived suppressor cells (MDSCs).^4,5  Importantly, there is no disagreement that the relative numbers of these cells expand during sepsis, a finding first reported by Monneret et al nearly 10 years ago.⁶  Where there is still disagreement in the sepsis field is whether outcome to sepsis is dependent on Tregs and their suppressor cell activities. For example, we demonstrated several years ago that both the proportion and the suppressor activity of CD4⁺CD25⁺FoxP3⁺ T cells are increased in sepsis, very similar to the results reported here by Cavassani.⁵  Despite these findings, neither we nor Ayala and colleagues were able to link this increase in Treg suppressor function with increased mortality during sepsis.^5,7  Additionally, Carrigan et al were unable to show any difference in mortality to Pseudomonas pneumonia when Tregs were depleted.⁸  To make matters more confusing, Chen and Oppenheim reported the complete opposite finding—that depleting Tregs in sepsis improved outcome.⁹ 

Despite the lack of consensus on the role of Tregs in sepsis, Cavassani et al in this issue of Blood demonstrate that the Treg expansion that occurs after sepsis results in the more rapid growth of a solid transplantable tumor.³  The concept that Tregs can regulate tumor growth is not necessarily novel, although the linking of sepsis and Treg expansion with tumor growth clearly is. When it comes to suppressor cells and tumor growth and metastasis, considerable research in the last decade has been centered on both Treg and MDSC populations.¹⁰  Only recently, though, has there been evidence that the MDSC population with suppressor cell function is increased in sepsis.⁴ 

Although the findings are convincing that Tregs play a role in the accelerated growth of established tumors after sepsis, the study raises a number of evocative questions. Unfortunately, the studies do not answer 2 inevitable questions: through what mechanisms do Tregs permit more rapid growth of an established solid tumor, and are Tregs the sole or primary agents of this response?

For the former question, the authors did report decreases in CD8⁺ IFN-γ and perforin expression in the draining lymph nodes of postseptic and control non–tumor-bearing and tumor-bearing mice.³  Unfortunately, the data are not antigen specific, but they do suggest that postseptic Tregs may be better at suppressing CD8⁺ T-cell responses than those Tregs isolated from control mice, which would not be a surprising finding.⁵  As CD8⁺ T cells are important in immune surveillance and to strengthen the authors argument that postseptic Tregs may be more potent at suppressing CD8⁺ T-cell responses than control animals, Cavassani et al adoptively transferred Tregs from postseptic animals or control animals along with naive CD8⁺ T cells in RAG^−/− hosts.³  As demonstrated in the report, tumors implanted in mice that were adoptively transferred with postseptic Tregs and naive CD8⁺ T cells were significantly larger than those tumors from control mice.³ 

The second question is much more problematic given the plethora of changes in both innate and adaptive immunity during sepsis. The challenge in studying the impact of post-sepsis immune suppression on solid tumor growth is the same challenge as studying sepsis immune suppression: how to understand the role of a single mediator or cell process in the context of a complex syndrome with aberrations in multiple suppressor cell and effector cell populations. The take home message that the authors wish to convey is that the expansion of Tregs and their increased suppressor activity during sepsis may create an immune suppressive environment that accelerates the growth of a solid transplantable tumor. These conclusions are well supported by their data, and the hypothesis provides a novel research direction for Tregs in the potentiation of cancer growth and inhibition of immune surveillance in the postseptic period. However, more conclusive mechanistic data will be needed to prove that these Tregs are indeed influencing the function of CD8⁺ T cells. In addition, as the authors themselves state, it is unknown what effect these postseptic Tregs are having on other cells known to have a role in tumor growth, such as NK cells.³  Also, the role of MDSCs and the interplay of these 2 strongly CD8⁺ T-cell immunosuppressive cell types need to be taken into account as both of these cell populations expand in the postseptic host. Ultimately, the answer will be surely more complex than proposed by the authors, but the studies represent a good start in this important direction.