Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies

Abstract

Immune checkpoint inhibitors (ICI) have shown great promise in a wide spectrum of adult solid and hematological malignancies, achieving objective tumor responses and prolonging survival. However, there is limited clinical success amongst pediatric patients. In this review, we summarize the current understanding of ICI and present an up-to-date overview of recent and ongoing clinical trials of ICI in pediatric malignancies. In addition, we will discuss immunologic and clinical difficulties in this young population, as well as future prospects for combination of ICI with other immune-based and conventional treatments.

Keywords: Cytotoxic T lymphocyte antigen-4 (CTLA-4); Immune checkpoint inhibitor; Immunotherapy; Programmed death receptor-1 (PD-1); Programmed death-ligand 1 (PD-L1).

Fig. 1

Resting T-cells rarely express CTLA-4, which is retained inside the secretory granules, but after TCR activation, CTLA-4 is up-regulated and emerges to the plasma membrane of T-cells and binds to B7 ligands (CD80 and CD86) on antigen presenting cells (APCs) with 10–100-fold higher avidity than CD28, resulting in reduced T-cell proliferation and lessened cytokine secretion [185,186]. CTLA-4 exerts TCR inhibitory signal through serine/threonine protein phosphatase 2 (PP2A) and Src-homology 2 domain-containing phosphatase 2 (SHP2), and induces inhibition of serine/threonine kinase AKT on the downstream of phosphatidylinositol-3-kinase (PI3K), resulting altered T-cell metabolism and decreased T-cell proliferation and activity [187,188]. Besides, CTLA-4 shortens the duration of immune synapses as a result of signal attenuation and integrin deactivation and increases the T-cell activation threshold by producing inhibitory signals in the early phase of tumorigenesis.

Fig. 2

PD-1 is also expressed on T-cells following TCR engagement and activation. PD-1 and PD-L1 ligation exerts inhibitory signals for lymphocyte activation. PD-1 modulates T-cell function through (a) direct antagonism of TCR signaling by recruiting Src-homology 2 domain-containing phosphatase (SHP)-1 and SHP-2 to tyrosine-based inhibitory motifs (ITM; immunoreceptor tyrosine-based motifs) in the PD-1 tail, (b) inhibition of PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway, implicating the role of PD-1 in metabolism, nutrient sensing, survival, and cell growth to cell cycle, (c) modulation of Ras pathway, linking PD-1 to cell cycle and reducing T-cell proliferation, (d) increased expression of basic leucin zipper transcription factor, activating transcription factor (ATF)-like transcription factor (BATF), which can repress expression of effector gene transcription [14,189,190]. Further, these signaling events impair T-cell motility and stability leading to unproductive immune synapses with APCs [170,191].

Fig. 3

Mechanisms of tumor immune escape. ‘Hot’ tumors (A) may escape through up-regulation of immune checkpoint molecules and Tregs, secretion of immunosuppressive factors, indoleamine-2,3-dioxygenase (IDO), or T-cell anergy. (B) Tumor intrinsic mechanism of escape in “cold tumors” by downregulation of MHC molecules, attraction of M2 tumor-associated macrophages (TAMs), alteration of the tumor microenvironment, discouraging T-cell homing either by subduing inflammation, or suppressing release of T-cell chemokines, or releasing inhibitory cytokines to impair the recruitment of immune cells to the tumor microenvironment, or by dysregulating oncogene pathways including PI3 kinase/PTEN/AKT, p53 and STAT3 signaling.