JITC Editor Picks
Ana Costa, Journal for ImmunoTherapy of Cancer 2022;10:e004807 (5 August 2022)
The immune microenvironment of neuroblastoma is incompletely understood, with studies to date relying on limited numbers of markers to characterize the constituents. Using a combination of single-cell transcriptomics as well as multicolor flow cytometry and immunohistochemistry, Ana Costa and colleagues provide a complete characterization of the neuroblastoma tumor microenvironment in the commonly used TH-MYCN transgenic mouse model and biopsies from human patients. Common across the mouse models and the human specimens were abundant macrophages and myeloid cells, with macrophages expressing genes consistent with a suppressive M2 phenotype and the myeloid population displaying signatures consistent with neutrophils and myeloid-derived suppressor cells. Myeloid cells isolated from murine tumors strongly inhibited CD4+ and CD8+ T cell proliferation in vitro, confirming their suppressive phenotype. Heterogeneous populations of cancer-associated fibroblasts were also present in both mouse and human tumors. The rare T cells present in the tumors all expressed at least one exhaustion marker, including LAG3, TIGIT, CTLA-4, TIM3, and PD-L1. The data not only confirm the relevance of the TH-MYCN model to the immunosuppressed human neuroblastoma microenvironment, but also offer a rich resource for potential target identification for future immune therapies.
Journal for ImmunoTherapy of Cancer 2022;10:e004325 (18 August 2022)
Hypoxia-induced upregulation of extracellular ectonucleases on cancer cells leads to an accumulation of adenosine in the tumor microenvironment, resulting in potent immunosuppression. Small molecule inhibitors of the key cell-surface ectonuclease CD39, which catalyzes the hydrolysis of ATP to AMP, are unfavorable drug candidates due to metabolic instability and lack of selectivity. Reasoning that approved ATP-competitive receptor tyrosine kinase inhibitors might also have activity against the ATP-binding site of CD39, Laura Schäkel et al identified ceritinib as a new chemotype of CD39 inhibitor in a repurposing screen. Out of the 50 compounds screened against in vitro preparations of CD39 expressed in umbilical cord membranes, the only hit with greater than 50% inhibition was the anaplastic lymphoma kinase (ALK) inhibitor ceritinib, which is approved in non-small cell lung cancer indications. Identical half maximal inhibitory concentrations in the micromolar range were observed across two different assays with substrate concentrations that varied by twofold. Surprisingly, characterization of the Michaelis constant and maximum reaction rate revealed that ceritinib inhibits CD39 in a non-competitive, allosteric manner. Consistent with the in vitro results, ceritinib inhibited extracellular ATP hydrolysis by primary human peripheral blood mononuclear cells, breast cancer and melanoma membrane preparations, as well as live cancer cells. These findings lay the groundwork for optimization of ceritinib as a modulator of adenosine-mediated immunosuppression.
Journal for ImmunoTherapy of Cancer 2022;10:e004417 (24 August 2022)
Since 2017, most patients with resectable, sentinel lymph node positive melanoma forgo complete lymph node dissection (CLND) based on no deficits in 3-year melanoma-specific survival and 5-year overall survival, respectively, in the MSLT-II and DeCOG-SLT trials. However, the registrational trials for adjuvant systemic immunotherapy for resectable melanoma, CheckMate 238 and EORTC1325/KEYNOTE-054, mandated CLND and outcomes for patients treated with adjuvant systemic therapy after a positive sentinel lymph node without a CLND are not known. In a multicenter retrospective analysis that included patients with sentinel lymph node positive melanoma treated at 21 centers in the USA, Europe, and Australia after the results from MSLT-II became available in 2017, Zeynep Eroglu and colleagues demonstrate that omitting CLND prior to adjuvant anti-PD-1 does not appear to negatively affect relapse-free survival. Interestingly, although the absolute rates of 2-year relapse-free survival were similar in this retrospective cohort to those seen in CheckMate 238 and EORTC1325/KEYNOTE-054, strikingly more frequent locoregional relapses were seen in the patients who did not undergo immediate CLND. This analysis provides important information on a major discrepancy between clinical trial conditions and real-world practice. Future trials and longer follow-up are needed to answer the open question of how to manage relapsed melanoma post-resection and adjuvant anti-PD-1.