NKG2D ligand expression in pediatric brain tumors

Abstract

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.

Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy

“…21 Previous studies have demonstrated that immune infiltrate in pediatric CNS tumors has no bearing on survival. 14 Furthermore, pediatric CNS tumors may not establish an immunosuppressive microenvironment as is seen in adult CNS tumors, 13 and instead reflect a failure of immune surveillance. It is not clear, however, whether impaired immune surveillance is the result of poor lymphocyte trafficking to the tumor site or minimal expression of ligands for activating immune receptors expressed by lymphocytes.…”

“…TMAs were constructed as previously described 13 and included triplicate cores from pediatric low-grade glioma (pLGG) (19 pilocytic astrocytoma, 4 ganglioglioma), pediatric high-grade cortical glioma (pHGG) (11 anaplastic astrocytoma, 16 GBM), DIPG (n = 9), and control (12 nontumor pediatric brain). Details can be found in the Supplementary Methods.…”

“…To date, there has been little investigation of the tumor microenvironment (TME) of pediatric CNS tumors, a critical first step in the rational development of effective immunotherapy strategies. However, in contrast to adult high-grade gliomas, which have extensive immune cell infiltration, 11 high-grade pediatric tumors often have a notable absence of a myeloid or lymphoid infiltrate [12][13][14] that fails to correlate with survival. 14 Because DIPG tumors are rarely surgically resected, tumor tissue from these patients is infrequently available; therefore most prior studies have not evaluated immune cell infiltration in DIPG patient tumors.…”

Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma

“…CCL3, CCL4) and absence of lymphocytes in primary tissue are consistent with the failure of DIPG-associated macrophages to trigger an effective anti-tumor immune response. Adding to the evidence for lack of an effective innate or adaptive immune response in pediatric high-grade gliomas, a previous study demonstrated the lack of NK cell infiltration into pediatric high-grade gliomas [ 16 ], although this study did not specifically investigate DIPG. An “immune cold” state of DIPG is also consistent with the lack of inflammatory cells in pediatric non-brainstem gliomas recently described [ 30 ].…”

Natural Killer Cells: Tumor Surveillance and Signaling

“…The differences between mouse and human are further amplified by the presence of an ITAM signaling motif in DAP12 and a YxxM motif in DAP10 ( Figure 2B and Table 5) [214,215]. Human NKG2D ligands are expressed in ovarian cancer, leukemia, colorectal cancer and pediatric brain cancers, amongst others [216][217][218][219][220]. Regardless of ligand expression, Groh et al [221] showed that soluble MIC (sMIC) shed by tumors impaired NKG2D mediated cytotoxicity by blocking receptor engagement and thus signaling [221,222].…”