Fueling Cancer Immunotherapy With Common Gamma Chain Cytokines

Abstract

Adoptive T cell transfer therapy (ACT) using tumor infiltrating lymphocytes or lymphocytes redirected with antigen receptors (CAR or TCR) has revolutionized the field of cancer immunotherapy. Although CAR T cell therapy mediates robust responses in patients with hematological malignancies, this approach has been less effective for treating patients with solid tumors. Additionally, toxicities post T cell infusion highlight the need for safer ACT protocols. Current protocols traditionally expand T lymphocytes isolated from patient tumors or from peripheral blood to large magnitudes in the presence of high dose IL-2 prior to infusion. Unfortunately, this expansion protocol differentiates T cells to a full effector or terminal phenotype in vitro, consequently reducing their long-term survival and antitumor effectiveness in vivo. Post-infusion, T cells face further obstacles limiting their persistence and function within the suppressive tumor microenvironment. Therapeutic manipulation of T cells with common γ chain cytokines, which are critical growth factors for T cells, may be the key to bypass such immunological hurdles. Herein, we discuss the primary functions of the common γ chain cytokines impacting T cell survival and memory and then elaborate on how these distinct cytokines have been used to augment T cell-based cancer immunotherapy.

Keywords: T cell; TRUCKs; adoptive cell transfer; chimeric antigen receptor; gamma chain cytokines.

Figure 1

Common γ chain cytokine signaling impacts the functional fate of T cells for adoptive cell transfer. The six members of the γc cytokine family (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) and the composition of their unique cytokine receptors. Signaling cascades from these receptors lead to distinct biological outcomes impacting differentiation, effector function and memory development of T cells.

Figure 2

Use of γc cytokines for ex vivo T cell expansion generates T cells with variable memory phenotypes. γc cytokines promote different biological programs that influence the differentiation of T cells. While IL-2 promotes robust proliferation it also promotes terminal effector differentiation. IL-7 and IL-15 maintain the homeostasis and survival of memory T cells and treatment ex vivo promotes a Tscm/Tcm phenotype. IL-21 slows T cell expansion but prevents differentiation and maintains a naïve-like T cell phenotype. With respect to antitumor immunity, less differentiated cell products are more therapeutic leading to the understanding that IL-2 is not the best option for ex vivo expansion.

Figure 3

Superior antitumor immunity of IL-2/IL-21-primed CAR T cells producing IL-7 and IL-15 at the tumor site. Generating TRUCKs ex vivo in the presence of IL-2 and IL-21 would prevent terminal differentiation, promote enhanced antitumor immunity with robust T cell proliferation. While at the tumor site, secretion of IL-7 and IL-15 would maintain TRUCK proliferation and memory function allowing for robust and persistent antitumor immunity against solid tumors.