Immune Monitoring during Therapy Reveals Activitory and Regulatory Immune Responses in High-Risk Neuroblastoma

Abstract

Despite intensive treatment, including consolidation immunotherapy (IT), prognosis of high-risk neuroblastoma (HR-NBL) is poor. Immune status of patients over the course of treatment, and thus immunological features potentially explaining therapy efficacy, are largely unknown. In this study, the dynamics of immune cell subsets and their function were explored in 25 HR-NBL patients at diagnosis, during induction chemotherapy, before high-dose chemotherapy, and during IT. The dynamics of immune cells varied largely between patients. IL-2- and GM-CSF-containing IT cycles resulted in significant expansion of effector cells (NK-cells in IL-2 cycles, neutrophils and monocytes in GM-CSF cycles). Nonetheless, the cytotoxic phenotype of NK-cells was majorly disturbed at the start of IT, and both IL-2 and GM-CSF IT cycles induced preferential expansion of suppressive regulatory T-cells. Interestingly, proliferative capacity of purified patient T-cells was impaired at diagnosis as well as during therapy. This study indicates the presence of both immune-enhancing as well as regulatory responses in HR-NBL patients during (immuno)therapy. Especially the double-edged effects observed in IL-2-containing IT cycles are interesting, as this potentially explains the absence of clinical benefit of IL-2 addition to IT cycles. This suggests that there is a need to combine anti-GD2 with more specific immune-enhancing strategies to improve IT outcome in HR-NBL.

The immune cell atlas of human neuroblastoma

“…Interestingly, in this study, large variations between patients existed and immune cell phenotypes related to both tumor suppression and support were detected. 76 The influence of different cancer therapies on immune cells in the broader cancer perspective has not been defined yet, with chemotherapy having both immune enhancing and inhibiting properties. 77 Furthermore, interpretation of survival analysis can be difficult since the outcome is highly dependent on the type of analysis, the number of patient samples, the distribution of outcome, which biomarkers are analyzed, and possible additional factors.…”

A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model

“…CD16 + cells represent a subpopulation of NK cells displaying cytotoxic activity higher than that exerted by the CD16 − population ( Orange, 2008 ; Myers and Miller, 2021 ). Since the infiltration and phenotype of NK cells have been correlated with prognosis and response to immunotherapy in NB tumors ( Melaiu et al, 2020 ; Szanto et al, 2021 ), it is crucial to dispose of a preclinical model that faithfully recapitulates the human pathology.…”

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

“…This resting, immature profile of NK cells recapitulates their previously described state in other tumors, designated as ‘arrested development’(42). NK cell dysfunction in neuroblastoma is not limited to the tumor microenvironment but has also been observed in peripheral blood of patients, throughout the treatment course(55). A recently published phase II trial adding anti-GD2 treatment, which is considered to rely at least partly on activity of NK cells(41), to conventional induction chemotherapy, observed improved early responses and event-free survival in comparison with historic reference cohorts(54).…”

“…cells in pre-treatment tumors -suggests that immunotherapy may be able to reverse or at least ameliorate the arrested state of NK cells (54), as also previously observed in peripheral blood of patients. (55). Still, NK cell dysfunctionality in neuroblastoma may warrant further investigations into parent-derived NK cell infusions in combination with anti-GD2.…”