Adjuvant IL-7 potentiates adoptive T cell therapy by amplifying and sustaining polyfunctional antitumor CD4+ T cells

Abstract

Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.

Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells

“…Additionally, transfection with constitutively-active STAT5 has been associated with superior anti-tumor activity in mouse models of malignancy, and CAR-T cells engineered toward increased STAT5 activity demonstrate improved proliferation and polyfunctionality while preventing terminal differentiation ( 71 , 72 , 74 , 75 , 86 ). Several studies have also demonstrated that ex-vivo expansion of antigen-specific T cells in the presence of IL-7, an upstream regulator of STAT5 activity, is associated with a STAT5-dependent increase in polyfunctional cells ( 69 – 74 , 85 , 87 – 89 ). This is of particular interest given that polyfunctional T cells have increased surface expression of IL-7R, which regulates IL-7 activity.…”

Frontline Science: Late CD27 stimulation promotes IL-7Rα transcriptional re-expression and memory T cell qualities in effector CD8+ T cells

“…Finally, our findings of CD27‐induced enhanced IL‐7R (both α and γc subunits) and augmented pSTAT5‐mediated signaling highlight the potential of targeting CD27–CD70 axis to enhance IL‐7 signaling for antiviral/antitumor immunotherapy. The preclinical and clinical application of rIL‐7 has been reported to result in enhanced T‐cell immunity, raising the prospect that IL‐7 signaling could mediate therapeutic benefits in the treatment of acute and chronic infections and cancer . Given the published clinical experience with the use of rhIL‐7 therapy so far is modest, enhancing IL‐7Rα by targeting CD27 may synergize with rhIL‐7 therapy to achieve optimized IL‐7 signaling especially in the elderly, leading to more favorable outcomes.…”

“…The preclinical and clinical application of rIL-7 has been reported to result in enhanced T-cell immunity, raising the prospect that IL-7 signaling could mediate therapeutic benefits in the treatment of acute and chronic infections and cancer. 3,4,30,31 Given the published clinical experience with the use of rhIL-7 therapy so far is modest, 32 enhancing IL-7R by targeting CD27 may synergize with rhIL-7 therapy to achieve optimized IL-7 signaling especially in the elderly, 33 leading to more favorable outcomes. Moreover, in comparison to rhIL-7 therapy that primarily targets steadystate T-cell populations and improves immune reconstitution through increasing thymic output and through Ag-independent homeostatic driven proliferation in the periphery, 30 CD27 stimulation promotes IL-7R in effector CD8 + T-cell population in an Ag-dependent manner and contributes to their long-term maintenance.…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Clinical trials revealed that IL-7 monotherapy resulted in expansion of CD8+ Tc and CD4+ Th cells, but not CD4+ Tregs [196,197]. Recently, Ding and co-authors showed that co-administration of IL-7 with tumour-reactive CD4+ Th cells promoted their expansion, persistence and anti-tumour activity in a mouse model, thus providing a rationale for using IL-7 as an adjuvant for CD4+ Th cell-based adoptive immunotherapy [198].…”