Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival

Abstract

Although great effort is being expended in the development of cancer immunotherapies, it is surprising that global lymphopenia and its various dimensions are not being systematically assessed in cancer patients. The incident pathologies associated with various immunosuppressed conditions such as those found in HIV infection have taught us that measuring various T cell populations including CD4 provides the clinician with a reliable measure for gauging the risk of cancer and opportunistic infections. Importantly, recent data emphasize the key link between lymphocyte T cell counts and overall survival in cancer patients receiving chemotherapy. Treatment of immunocompromised patients with interleukin-7 (IL-7), a critical growth and homeostatic factor for T cells, has been shown to produce a compelling profile of T cell reconstitution. The clinical results of this investigational therapy confirm data obtained from numerous preclinical studies and demonstrate the long-term stability of this immune reconstitution, not only on CD4 but also on CD8 T cells, involving recent thymic emigrants as well as naive, memory, and central memory T cells. Furthermore, IL-7 therapy also contributes to restoration of a broadened diversity of the T cell repertoire as well as to migration of these cells to lymph nodes and tissues. All these properties support the initiation of new clinical studies aimed at reconstituting the immune system of cancer patients before or immediately after chemotherapy in order to demonstrate a potentially profound increase in overall survival.

Fig. 1

IL-7 a key factor in thymopoiesis and T cell periperal homeostasis. IL-7 receptor is expressed on common lymphoid progenitors (CLP) cells in the bone marrow and is essential for maintenance or progenitor pool for both B and T cells. During T cell development in the thymus IL-7 is involved at different stages of T cell proliferation and positive/negative selection. Following thymic export, recent emigrant T cells (RTE) are incorporated to the periphery. In the periphery, IL-7 is a major anti-apoptotic/survival factor of T cells through elevation of Bcl-2 expression. It also controls homeostatic and antigen-driven expansion of both CD4 and CD8 T cells. Its capacity to augment the immune response to weak or low affinity antigens will lead to the recognition of tumoral antigens. The Th1 response directly target tumoral cells. Following antigen driven expansion of activated T cells, a small population of effector cells become long-lived memory T cells expressing high levels of IL-7 receptor, the long-lasting anti-tumoral response. IL-7 by controlling thymopoiesis and peripheral homeostasis as well as antigen response is a critical factor for the immune system

Fig. 2

Possible mechanisms of action of IL-7 immunotherapy in oncology. IL-7 immunotherapy increases both CD4 and CD8 T cell subsets (Levy et al.). In non-lymphopenic recipients, this increase is transient and return to baseline (unpublished data CONVERT study); while in lymphopenic patients, a progressive restoration was observable with a sustained higher T cell count at 1 year post-treatment [74]. T-lymphocyte infiltration was demonstrated in lymph nodes, gut, and skin lymphoid tissue [60] in primates following IL-7 treatment. The cytokine lead to an upregulation of homing chemokine receptors on T cells including CXCR4, CCR6, and CCR9 coupled with increased chemokine levels in tissues (CCL19, CCL20, CCL21, and CCL25) and plasma (CCL3, CCL4, and CXCL12). The teams of Li et al. and Pellegrini et al., elegantly demonstrated that IL-7 treatment of mice induces a massive T cell infiltration in murine tumor leading to an enhanced anti-tumor protection correlated with an increased number of activated dendritic cells [61, 62]. Moreover, IL-7 will decrease the immunosuppressive environment in the tumor by decreasing TGFbeta secretion a key cytokine for immunosuppressive Treg. By increasing the number of tumor reactive T including cells with a memory phenotype cells and decreasing immunosuppression will result in a persistent and long-lasting anti-tumor T cell response

Fig. 3

Impact of IL-7 on T cell repertoire. IL-7 has a major role in preserving the naïve T cell repertoire by increasing thymopoiesis and cell viability in absence of antigen stimulation. Thymopoiesis increase was demonstrated by the increase of TRECs following IL-7 immunotherapy in HIV patients. By inducing a higher rate of thymocyte proliferation, the cytokine generates more diverse TCR rearrangement contributing to an increase of RTE and naive T cell subsets in the periphery. An increase of the T cell pool diversity was demonstrated by TCR beta combinational diversity in HIV-infected patients treated with IL-7(manuscript in preparation INSPIRE 1 study). Peripheral expansion of pre-existing T cells probably contributes to the TCR repertoire diversification observation. By increasing thymus activity, output, and peripheral expansion of produced cells IL-7 potentially increase T cell repertoire diversity

Fig. 4

Clinical trial design involving IL-7 immunotherapy. As lymphopenia was identified as a prognosis factor for overall survival and tumor progression in patients with advanced cancer, cycles of IL-7 could be used before chemotherapy intervention to restore global immunity. Two different types of cancer are envisaged here: solid tumor and bone marrow transplantation. In metastatic patients presenting a chemotherapy-induced lymphopenia, cycle of IL-7 before or during chemotherapy will counteract the lymphopenia effect and preserve T cell survival. Following T cell depletion in bone marrow transplanted patients, multiple cycles of IL-7 will be necessary to recover a competent immune system and reach a less life-threatening window