Predicting the Efficacy of Immune-Based Therapies for Pediatric Solid Tumors

A number of possible immunotherapies for cancer are based on T-cells that can target and kill tumors. These cytotoxic T lymphocytes (CTLs) can only recognize tumor cells, though, if an antigen is expressed in the context of major histocompatibility complex (MHC) class I (encoded on the human leukocyte antigen (HLA) gene in humans). Tumors that downregulate HLA class I evade the CTLs.

It could be very important, then, to know the status of expression of HLA class I and its required associated β-2-microglobulin (B2M) molecule in various tumors to assess how susceptible the tumors would be to the T-cell-based therapies. High expression indicates the possibility that a CTL would engage a tumor; little or no expression indicates little or no possibility for engagement. Low expression, however, is thought to be necessary for the innate immune system’s natural killer (NK) cells to be activated, so it could mean that an NK cell-based immunotherapy may be effective.

In a recently published study, clinician-researchers at Nationwide Children’s Hospital have characterized HLA class I and B2M in 18 different types of pediatric solid tumors — and the study’s authors have proposed a “CTL target score” in an attempt to predict tumor susceptibility to T-cell-based therapies.

Among the findings were that pediatric brain tumors including glioblastoma multiforme and atypical teratoid/rhabdoid tumors (AT/RT) tended to show greater HLA class I and B2M gene and protein expression than other cancers. Neuroblastomas and alveolar rhabdomyoscarcomas tended to have lower expressions of both molecules.

The researchers also demonstrated that some tumor types can have widely varying HLA class I and B2M expression, indicating tumor heterogeneity, so individual patients’ tumors may require individual evaluations. Detailed figures and tables illustrating the expressions of the tumors analyzed are in the study, published in the journal Pediatric Blood & Cancer.

“Our hope is that we can ultimately use this clinically,” says Kellie Haworth, MD, a research fellow in the Division of Hematology, Oncology and Blood and Marrow Transplant at Nationwide Children’s and the lead author of the study. “This immunologic profile and the CTL target score could tell you if it’s worth it to try a T-cell-based versus an NK cell-based therapy.”

The researchers first determined HLA class I and B2M gene expression in tumors using data from the National Cancer Institute’s pediatric preclinical testing program tumor samples. Five representative cell lines were chosen to culture and perform flow cytometric analysis, which showed HLA protein expression correlated with gene expression. Researchers also performed immunochemistry for protein expression of both HLA class I and B2M on 18 solid tumor types using tumor samples from Nationwide Children’s patients.

The CTL target score takes into account both HLA class I and B2M expression, because B2M must also be present for HLA Class I to fold correctly and functionally present the antigen to CTLs. The formulas for calculating scores, and the calculations for the tumors themselves, can be found in the study’s supplementary materials online. The authors stress that the target score still needs to be tested prospectively in clinical trials.

Researchers also evaluated whether HLA class I downregulation, which allows the cancer cells to escape CTLs, is reversible in some representative pediatric cancer cell lines. Variation was found here as well. For example, HLA class I expression could be increased in one AT/RT cell line with exposure to interferon gamma and histone deacetylase inhibitors, while another AT/RT cell line had little increase with interferon gamma and none with deacetylase inhibitors.

Nationwide Children’s researchers are continuing to study the immunologic profiles of individual tumor types and are moving to validate the CTL target scoring.