New insights into the stemness of adoptively transferred T cells by γc family cytokines

Abstract

T cell-based adoptive cell therapy (ACT) has exhibited excellent antitumoral efficacy exemplified by the clinical breakthrough of chimeric antigen receptor therapy (CAR-T) in hematologic malignancies. It relies on the pool of functional T cells to retain the developmental potential to serially kill targeted cells. However, failure in the continuous supply and persistence of functional T cells has been recognized as a critical barrier to sustainable responses. Conferring stemness on infused T cells, yielding stem cell-like memory T cells (TSCM) characterized by constant self-renewal and multilineage differentiation similar to pluripotent stem cells, is indeed necessary and promising for enhancing T cell function and sustaining antitumor immunity. Therefore, it is crucial to identify TSCM cell induction regulators and acquire more TSCM cells as resource cells during production and after infusion to improve antitumoral efficacy. Recently, four common cytokine receptor γ chain (γc) family cytokines, encompassing interleukin-2 (IL-2), IL-7, IL-15, and IL-21, have been widely used in the development of long-lived adoptively transferred TSCM in vitro. However, challenges, including their non-specific toxicities and off-target effects, have led to substantial efforts for the development of engineered versions to unleash their full potential in the induction and maintenance of T cell stemness in ACT. In this review, we summarize the roles of the four γc family cytokines in the orchestration of adoptively transferred T cell stemness, introduce their engineered versions that modulate TSCM cell formation and demonstrate the potential of their various combinations.

CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival

“…Interleukins, particularly IL2, IL7, and IL15, are essential for the proliferation and survival of CAR-T cells. 44 The co-expression of these interleukins with chemokine-modified CAR-T cells has made promising advancements. Specifically, 7 × 19 CAR-T cells have enhanced dendritic and T cell infiltration and CAR-T cell survival.…”

Advances in IL-7 Research on Tumour Therapy

“…Adoptive T cell therapy (ACT) has demonstrated remarkable effectiveness in combating tumours. This treatment depends on a reservoir of functional T cells capable of continually targeting and destroying tumour cells [ 128 ]. However, a persistent shortage of functional T cells has been recognised as a significant obstacle to achieving a lasting response.…”

“…However, a persistent shortage of functional T cells has been recognised as a significant obstacle to achieving a lasting response. Equipping infused T cells with stem-like qualities to produce memory T cells with the ability to self-renew and differentiate in multiple ways, akin to pluripotent stem cells, is crucial and holds great promise for improving T cell function and sustaining anti-tumour immunity [ 128 ].…”