Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state

Abstract

Rewiring exhausted CD8 T cells (TEX) towards more functional states is a major goal of cancer immunotherapy but has proven challenging due to the epigenetic stability of TEX. Indeed, TEX are epigenetically programmed by the transcription factor Tox. However, epigenetic changes continue to occur as TEX transition from progenitor (TEXprog), to intermediate (TEXint) and terminal (TEXterm) subsets, suggesting potential developmental flexibility in mature TEX subsets. By examining the transition of TEXprog into TEXint cells, we discovered a reciprocally antagonistic circuit between Stat5a and Tox in TEX cells. Stat5-activity controlled TEXint development, antagonized Tox, and instigated partial effector biology. Stat5 was also essential for TEX reinvigoration by PD-1 blockade. Indeed, temporal induction of Stat5-activity in TEX using an orthogonal IL-2/IL2Rb-pair fostered TEXint cell accumulation and synergized with PD-L1 blockade. Constitutive Stat5a activity (STAT5CA) antagonized Tox-dependent TEX epigenetic programming to generate a durable hybrid effector/NK-like population with enhanced tumor control. Finally, enforcing Stat5-signals in established TEXprog partially rewired the TEX epigenetic landscape towards the effector/memory lineage. Together, these data highlight therapeutic opportunities of manipulating Stat5 to rewire TEX towards a durably protective hybrid program.

Tregs constrain CD8+T cell priming required for curative intratumorally anchored anti-4-1BB immunotherapy

“…5C). Recent literature has highlighted a role for IL-2, or more broadly Stat5a activity, in amplifying T cell populations that drive responses to checkpoint blockade ( 57–59 ). Taken together, the tumor transcriptional data support the notion that Tx + αCD4 drives a robust cytotoxic T cell program leading to tumor rejection.…”

“…5C). Recent literature has highlighted a role for IL-2, or more broadly Stat5a activity, in amplifying T cell populations that drive responses to checkpoint blockade (57)(58)(59).…”

Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens

“…ProjecTILs (version 2.0) was used to map our data onto scRNA-Seq data from Miller et al (45). F gsea (version 1.26.0) was used to perform GSEA on the CD8 expressing T cells using Tex gene signatures from Miller et al and Beltra(45, 59). GSVA (version 1.48.2) was used to perform GSVA on the CD8 expressing T cells using Tex gene signatures from Miller et al and Beltra et al The extent of clonal expansion per cluster was quantified using the StartracDiversity() function from scRepertoire (version 1.10.0).OT1 T cells were identified by searching the TCR repertoire for cells containing both the OT1 CDR3 Tcra amino acid sequence (CAASDNYQLIW) and the OT1 CD3R Tcrb amino acid sequence (CASSRANYEQYF).…”

T‐cell heterogeneity, progenitor–progeny relationships, and function during latent and chronic viral infections

“…123,124 A potential mechanism trough which IL-2 promotes differentiation of effector-like cells is through STAT5 signaling, which suppresses TOX expression, which in turn antagonizes the TOX-induced exhaustion epigenetic program, enabling the acquisition of an effector-like epigenetic landscape. 125 Additionally, IL-2 induces upregulation of the alarmin (IL-33) receptor ST-2, 123 which has been shown to promote TCF-1 expression in CD8 T cells. 126 Soluble cytokines produced in the inflammatory environment can also inhibit the differentiation of TCF1 + cells.…”

“…However, a recent study showed that IL‐2 signaling through CD25 acts synergistically with checkpoint blockade by remodeling the epigenetic landscape of TCF1 + cells 123,124 . A potential mechanism trough which IL‐2 promotes differentiation of effector‐like cells is through STAT5 signaling, which suppresses TOX expression, which in turn antagonizes the TOX‐induced exhaustion epigenetic program, enabling the acquisition of an effector‐like epigenetic landscape 125 . Additionally, IL‐2 induces upregulation of the alarmin (IL‐33) receptor ST‐2, 123 which has been shown to promote TCF‐1 expression in CD8 T cells 126 …”