Hijacked helpers: Tr1 cells fuel immune escape in B-ALL Free

In this issue of Blood, Venkatesh et al¹ demonstrate that in B-cell acute lymphoblastic leukemia (B-ALL), leukemia cells induce tumor-reactive TIM3⁺ CD4⁺ T cells to adopt immunosuppressive type-1 regulatory (Tr1) states, thereby impairing immune control and promoting disease progression. This finding builds on prior evidence that elevated TIM3⁺FOXP3^– CD4⁺ T-cell frequencies at diagnosis correlate with higher relapse risk, highlighting the need to better understand their identity and function.

Tr1 cells, first described by Maria Grazia Roncarolo et al,² are a distinct subset of regulatory T cells (Tregs) characterized by their ability to suppress immune responses through the secretion of high levels of interleukin-10 (IL-10) and transforming growth factor β, without expressing the transcription factor FOXP3, that is typical of conventional Tregs.³ Tr1 cells are primarily induced in the periphery in response to chronic antigen exposure and are essential for maintaining immune homeostasis, promoting tolerance to self-antigens, and preventing excessive inflammation or autoimmunity.⁴ 

In cancer, Tr1 cells play a complex and context-dependent role. Although their immunosuppressive function can help limit chronic inflammation, that may otherwise promote tumor progression, they can also impair effective antitumor immunity, thereby facilitating immune evasion by cancer cells.⁵ Elevated frequencies of Tr1-like cells have been reported across various tumor types, where they contribute to the formation of an immunosuppressive tumor microenvironment, thereby promoting immune escape.⁶ 

Recent studies have identified Tr1 cells with cytotoxic functions, further complicating their role in cancer. In chronic lymphocytic leukemia (CLL), IL-10–producing CD4⁺ T cells exhibiting a Tr1-like transcriptional profile, which is driven by the transcription factor eomesodermin (EOMES), accumulate in lymph nodes and possess cytotoxic properties.⁷ In a mouse model of CLL, these Tr1 cells depend on both EOMES and IL-10 receptor (IL-10R) signaling to mediate antileukemia activity.

Conversely, a recent study demonstrated that high-dose major histocompatibility complex class II neoantigen vaccination induces cytotoxic Tr1 cells that suppress antitumor responses by selectively killing antigen-presenting dendritic cells, ultimately inhibiting tumor rejection.⁸ These findings highlight the dual and sometimes opposing roles of Tr1 cells in cancer immunity and underscore the need for therapeutic strategies that can precisely modulate their function. A better understanding of Tr1 biology is therefore essential for advancing cancer immunotherapy.

How the immune system interacts with B-ALL, and whether it can effectively control or clear the disease, has remained a controversial question in cancer immunology. Unlike many solid tumors, where T-cell infiltration is often linked to favorable prognosis, B-ALL presents a more ambiguous picture: immune responses are detectable, yet relapses are common and difficult to predict. One key missing piece has been understanding the functional states of T cells in the leukemic microenvironment and how leukemic cells may coopt them. The study by Venkatesh et al makes a significant contribution to resolving this issue by identifying a specific population of Tr1 cells that arise in response to B-ALL and suppress antileukemic immunity.

Using single-cell RNA sequencing of human B-ALL samples, the authors identified a population of TIM3⁺ CD4⁺ T cells with a transcriptional signature consistent with Tr1 cells, characterized by IL-10 production, lack of FOXP3, and expression of coinhibitory receptors. Importantly, this Tr1 signature correlated with reduced survival of patients, suggesting a role in promoting disease progression. The study further validated these findings in mouse models of B-ALL and showed that leukemic blasts actively induce the Tr1 phenotype in CD4⁺ T cells in vitro. Functional assays confirmed that these induced Tr1 cells suppress CD8⁺ T-cell proliferation, providing a direct link to impaired cytotoxic responses.

A particularly novel aspect of the study is the development of a mouse model with transgenic CD4⁺ T cells expressing a T-cell receptor previously identified as expanded clonotype in the B-ALL mouse model. These T cells recognize an antigen derived from human ABL kinase, a known driver in BCR-ABL⁺ B-ALL, making this a physiologically relevant model for studying B-ALL–specific T-cell responses. However, rather than supporting tumor clearance, these ABL-specific CD4⁺ T cells adopt a Tr1 phenotype within the leukemic microenvironment. Strikingly, the authors propose that leukemic cells evade immune control by mimicking the cross talk between CD4⁺ T cells and hematopoietic stem cells (HSCs), which are normally regulated by Tr1 cells to eliminate transformed HSCs from the hematopoietic system, thereby hijacking an immunosurveillance mechanism.

The findings are both novel and mechanistically insightful. They suggest that Tr1 polarization of CD4⁺ T cells is not merely a consequence of immune dysfunction but is actively driven by leukemia as a means of immune evasion. Moreover, the data imply that the immune system's endogenous response to leukemia may be maladaptively protective, tolerating rather than eliminating the malignancy.

Therapeutically, the study explored combination treatment of the ABL kinase inhibitor nilotinib with IL-10R blockade or immune checkpoint inhibition. Although the addition of anti–IL-10R modestly reduced Tr1 development, it did not improve disease control. A potential explanation for this comes from a recently described role of IL-10R signaling in preventing CD8⁺ T-cell exhaustion in CLL,⁹ which likely compensates for the beneficial effect of this treatment on Tr1 development.

However, the combination of nilotinib with anti–programmed death-ligand 1 (PD-L1) significantly reshaped the CD4⁺ T-cell landscape, favoring T helper 1 (Th1) cell differentiation over Tr1 and eradicating residual disease. Unexpectedly, only minimal effects on the transcriptional states of CD8⁺ T cells were observed, suggesting that anti–PD-L1 treatment acts via modulating CD4⁺ T cells. These findings highlight a potential clinical avenue: reprogramming CD4⁺ T-cell fate as a complement to existing cytotoxic or immune therapies.

Outstanding questions remain. How broadly applicable is this mechanism across B-ALL subtypes? Can the Tr1/Th1 axis be manipulated in patients safely and effectively? What other factors, metabolic, stromal, or epigenetic, contribute to Tr1 induction in leukemia? Addressing these issues will be key for translating these findings into improved clinical outcomes.

Overall, this study sheds light on a previously underappreciated mechanism of immune suppression in B-ALL and opens new directions for leveraging CD4⁺ T-cell plasticity in leukemia immunotherapy.

Conflict-of-interest disclosure: The author declares no competing financial interests.