Thymic derived lymphocytes, T cells, are essential elements of the immune system. They directly mediate immune responses to viral infection, cancer and transplanted tissues, and are necessary to generate and maintain immune memory following infection or vaccination. Cancer patients routinely experience depletion of T cells as a result of cancer itself and/or cytotoxic therapies administered to treat cancer. Unlike most blood cells, T cells cannot be effi ciently regenerated, leaving many cancer patients with depleted immune systems for years following completion of cancer therapy. Studies conducted over the last 15 years within the NCI Intramural Research Program have elucidated several fundamental concepts that shed light on the mechanisms by which T cells are regenerated in humans, and these have implicated interleukin-7 (IL-7) as a master regulator of T cell homeostasis.

• T cells can be regenerated via thymic-dependent or thymic-independent pathways, with age being the primary determining factor in which pathway is utilized. Children and young adults typically retain thymic function and show full T cell immune reconstitution within 1-2 years of completing therapy. In contrast, most adults show limited thymic function and typically regenerate T cells primarily via thymic-independent pathways. As a result, adults often experi- diminished immune function for several years following completion of cancer therapy.
• Interleukin-7 is necessary for both thymic-dependent and thymic-independent T cell regeneration. Humans experiencing T cell depletion have elevated levels of interleukin-7 in their tissues and serum, which is strongly inversely correlated with CD4+ counts. The clinical implications of chronically elevated levels of IL-7 remain unknown.
• Elevated interleukin-7 levels, and other less well-characterized changes in immune physiology, occur in response to lymphopenia, and enhance the effectiveness of adoptive cell therapies administered to lymphopenic hosts. Because of this, many immunotherapy trials for cancer currently incorporate a step aimed at depleting lymphocytes prior to adoptive immunotherapy.
• Preclinical and fi rst in human clinical studies have identifi ed interleukin-7 as a promising therapeutic. In animals, interleukin-7 potently augments responses to tumor vaccines. In humans, administration of interleukin-7 induces widespread increases in T cell numbers, preferentially expanding the “youngest” T cells and resulting in an anti-aging effect on T cell populations. IL-7’s capacity to increase T cell numbers appears does not appear to be diminished with increasing patient age. Unlike interleukin-2, which can also increase CD4+ T cell numbers, interleukin-7 is virtually non-toxic and does not selectively increase suppressor T cells.

Cover Image: Protein Data Bank Model of IL-7 Engaging the IL7R on the surface of a T cell.

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