InVivoMAb anti-human IFNγ

Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum-associated endophytic fungi, as a potent enhancer of Th9 cell differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell-dependent tumor control and enhanced the efficacy of human Th9 CAR T cell therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.

β-adrenergic signaling has been suggested to promote tumor growth, and β-blockers are being evaluated for repurposing for cancer treatment. Here, we identify a β-adrenergic signaling axis involved in metastasis formation. We show that the β-blocker propranolol has strong anti-metastatic activity in multiple murine models, with this effect being completely dependent on CD4 + T cells and independent of NK or CD8 + T cells. We also observe that CD4 + T cells are required for the anti-tumor effect of propranolol in a syngeneic subcutaneous model of colon cancer. Mechanistically, propranolol induces a Th1-polarized and cytotoxic CD4 + T cell response, which requires MHC class II expression by cancer cells for full efficacy. We also report propanolol-driven systemic changes in the monocyte compartment, and upon depletion of monocytes, propranolol loses its anti-tumor effects. Finally, we show that propranolol treatment synergizes with anti-CTLA-4 therapy to further enhance CD4 + T cell infiltration and control metastasis. Thus, we show that β-adrenergic signaling limits CD4 T cell-mediated anti-tumor immunity, highlighting the potential of repurposing β-blockers for cancer treatment.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

T cell engagers represent a novel promising class of cancer-immunotherapies redirecting T cells to tumor cells and have some promising outcomes in the clinic. These molecules can be associated with a mode-of-action related risk of cytokine release syndrome (CRS) in patients. CRS is characterized by the rapid release of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6 and IL-1β and immune cell activation eliciting clinical symptoms of fever, hypoxia and hypotension. In this work, we investigated the biological mechanisms triggering and amplifying cytokine release after treatment with T cell bispecific antibodies (TCBs) employing an in vitro co-culture assay of human PBMCs or total leukocytes (PBMCs + neutrophils) and corresponding target antigen-expressing cells with four different TCBs. We identified T cells as the triggers of the TCB-mediated cytokine cascade and monocytes and neutrophils as downstream amplifier cells. Furthermore, we assessed the chronology of events by neutralization of T-cell derived cytokines. For the first time, we demonstrate the contribution of neutrophils to TCB-mediated cytokine release and confirm these findings by single-cell RNA sequencing of human whole blood incubated with a B-cell depleting TCB. This work could contribute to the construction of mechanistic models of cytokine release and definition of more specific molecular and cellular biomarkers of CRS in the context of treatment with T-cell engagers. In addition, it provides insight for the elaboration of prophylactic mitigation strategies that can reduce the occurrence of CRS and increase the therapeutic index of TCBs.