Skin Effector Memory T Cells Do Not Recirculate and Provide Immune Protection in Alemtuzumab-Treated CTCL Patients

Alemtuzumab depletes malignant T cells but spares skin resident effector memory T cells, treating L-CTCL without increased risk of infection. Resolving Cutaneous T Cell Lymphoma Becoming more active figures prominently in many New Year’s resolutions. We vow to get off the couch, or up from the lab bench, and get in shape. Yet, after a 2- to 3-week frenzy, spaces appear in gym parking lots as most people resume their sedentary life-styles. Some but not all memory T cells mimic this cyclic action. Clark et al. now exploit this difference to successfully treat cutaneous T cell lymphoma (CTCL) without increasing patients’ risk of infection. CTCL is a cancer of skin-homing T cells that can either be restricted to the skin—mycosis fungoides (MF)—or extend to the blood—leukemic CTCL (L-CTCL). MF and L-CTCL are caused by malignancies in two different types of memory T cells: skin resident effector memory T cells (TEM) and central memory T cells (TCM), respectively. Clark et al. found that treating patients with a low dose of alemtuzumab—a monoclonal antibody to CD52, a protein found on the surface of some mature lymphocytes—has a therapeutic effect on L-CTCL but not MF. Indeed, alemtuzumab depleted all T cells, both benign and malignant, from the blood; however, in the skin, only TCM were depleted with alemtuzumab treatment. This effect depended on the presence of neutrophils—phagocytic cells found in the blood but rare in normal skin—which suggests that TCM but not TEM recirculate in the blood. Importantly, the remaining skin resident TEM in the L-CTCL patients may have a protective function, because risk of infection was not heightened in the treated patients. Thus, alemtuzumab destroys the more active malignant cells while sparing the more sessile population, resulting in cancer therapy with retained immunity and, hopefully, the chance for these patients to break many more New Year’s resolutions. Cutaneous T cell lymphoma (CTCL) is a cancer of skin-homing T cells with variants that include leukemic CTCL (L-CTCL), a malignancy of central memory T cells (TCM), and mycosis fungoides (MF), a malignancy of skin resident effector memory T cells (TEM). We report that low-dose alemtuzumab (αCD52) effectively treated patients with refractory L-CTCL but not MF. Alemtuzumab depleted all T cells in blood and depleted both benign and malignant TCM from skin, but a diverse population of skin resident TEM remained in skin after therapy. T cell depletion with alemtuzumab required the presence of neutrophils, a cell type frequent in blood but rare in normal skin. These data suggest that TCM were depleted because they recirculate between the blood and the skin, whereas skin resident TEM were spared because they are sessile and non-recirculating. After alemtuzumab treatment, skin T cells produced lower amounts of interleukin-4 and higher amounts of interferon-γ. Moreover, there was a marked lack of infections in alemtuzumab-treated L-CTCL patients despite the complete absence of T cells in the blood, suggesting that skin resident TEM can protect the skin from pathogens even in the absence of T cell recruitment from the circulation. Together, these data suggest that alemtuzumab may treat refractory L-CTCL without severely compromising the immune response to infection by depleting circulating TCM but sparing the skin resident TEM that provide local immune protection of the skin.