EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

The transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4+T-cells, which has been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4+T-cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. This was in line with an observed expansion of EOMES-positive CD4+T-cells in leukemic Eµ-TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription of IL-10, but rather controls a unique differentiation program in CD4+T-cells. Moreover, EOMES was necessary for the accumulation of a specific CD4+T-cell subset that expresses IFNγ and IL-10, as well as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenicRag2-/-mice showed that EOMES-deficient CD4+T-cells were inferior in controlling TCL1 leukemia development compared to wildtype T-cells, even though expansion ofEomes-/-CD4+T-cells was observed. We further showed that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, asIl10rb-deficient CD4+T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-1+CD4+T-cells contribute to CLL control in an EOMES- and IL-10R-dependent manner.