Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

Abstract

Neuroblastoma grows within an intricate network of different cell types including epithelial, stromal and immune cells. The presence of tumor-infiltrating T cells is considered an important prognostic indicator in many cancers, but the role of these cells in neuroblastoma remains to be elucidated. Herein, we examined the relationship between the type, density and organization of infiltrating T cells and clinical outcome within a large collection of neuroblastoma samples by quantitative analysis of immunohistochemical staining. We found that infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma. A variable structural organization and different concurrent infiltration of T-cell subsets were detected in tumors with various outcomes. Low-risk neuroblastomas were characterized by a higher number of proliferating T cells and a more structured T-cell organization, which was gradually lost in tumors with poor prognosis. We defined an immunoscore based on the presence of CD3, CD4 and CD8 infiltrating T cells that associates with favorable clinical outcome in MYCN-amplified tumors, improving patient survival when combined with the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) status. These findings support the hypothesis that infiltrating T cells influence the behavior of neuroblastoma and might be of clinical importance for the treatment of patients.

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…37 Further, for most tumor types there is a large body of data indicating that the concentration of T cells in tumors (TIL) correlates with favorable outcome. [38][39][40] In addition to antitumor efficacy in vivo, increased tumor cell killing activity of combination treatment-derived splenocytes ex vivo suggest the presence of active antitumor T cells on a systemic level. Previously, we have shown that adenovirus improved the efficacy of adoptive T-cell transfer in mice by increasing the number of IFNg-expressing CD8…”

Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens

“…For example, Galon et al described the combination of CD8 + cellular infiltrates and CD45RO + cellular infiltrates to formulate a prognostically significant "immunoscore" in colon cancer. 27 In fact, naturally occurring tumorinfiltrating lymphocytes have been associated with better patient survival in numerous cancer types [28][29][30] and may also correlate with better responsiveness to checkpoint inhibition. 31 In addition, predictive biomarkers of response are likely to depend on the type of immunotherapy used.…”

The challenge of defining “ultra‐high‐risk” neuroblastoma

“…Another, as yet relatively underexplored, area for prognostic factors relates to the host and tumor microenvironment rather than factors intrinsic to tumor cells themselves. For example, the extent of tumor infiltration by T cells or macrophages is correlated with outcome. Expression of different isoforms of the NK‐cell receptor NKp30 also correlates with EFS in patients with HR‐NBL who have responded to induction chemotherapy .…”

“…Of these three possible endpoints (A, B, or C), the continuous time‐to‐event endpoint would appear to be the most informative. In an analysis of INRG data, an approach using a binary endpoint [B] failed and was replaced by a successful analysis with a continuous time‐to‐event endpoint [A]. In an analysis exploring the potential utility of copy‐number profile for risk substratification, a binary endpoint [C] was used to identify a signature of UHR‐NB, but this signature was not validated in a separate patient cohort …”