Abstract
In multiple tumor types, prediction of response to immune therapies relates to the presence, distribution and activation state of tumor infiltrating lymphocytes (TILs). Although such therapies are, to date, unsuccessful in gliomas, little is known on the immune contexture of TILs in these tumors. We assessed whether low and high-grade glioma (LGG and HGG, grade II and IV respectively) differ with respect to number, location and tumor reactivity of TILs; as well as expression of molecules involved in the trafficking and activation of T cells. Intra-tumoral CD8 T cells were quantified by flow cytometry (LGG: n = 12; HGG: n = 8) and immunofluorescence (LGG: n = 28; HGG: n = 28). Neoantigen load and expression of Cancer Germline Antigens (CGAs) were assessed using whole exome sequencing and RNA-seq. TIL-derived DNA was sequenced and the variable domain of the TCRβ chain was classified according to IMGT nomenclature. QPCR was used to determine expression of T cell-related genes. CD8 T cell numbers were significantly lower in LGG and, in contrast to HGG, mainly remained in close vicinity to blood vessels. This was accompanied by lower expression of chemo-attractants CXCL9, CXCL10 and adhesion molecule ICAM1. We did not observe a difference in the number of expressed neoantigens or CGAs, nor in diversity of TCR-Vβ gene usage. In summary, LGG have lower numbers of intra-tumoral CD8 T cells compared to HGG, potentially linked to decreased T cell trafficking. We have found no evidence for distinct tumor reactivity of T cells in either tumor type. The near absence of TILs in LGG suggest that, at present, checkpoint inhibitors are unlikely to have clinical efficacy in this tumor type.
Highlights
Diffuse gliomas are the most common type of primary brain cancer in adults
We have made a comprehensive inventory whether low-grade gliomas (LGG) and high-grade tumor (HGG) differ with respect to number, location and tumor reactivity of tumor-infiltrating lymphocytes (TILs); as well as expression of molecules involved in the trafficking and activation of T cells
We observed that T cell numbers were decreased in LGG by approximately 5 fold when compared to HGG (Figs 1b, S1)
Summary
Diffuse gliomas are the most common type of primary brain cancer in adults. Currently, they are classified based on histological and genetic features into oligodendroglioma, astrocytoma and glioblastoma[1]. Absent or limited response to checkpoint inhibitors may be the result of a reduced antigenicity (tumor mutation burden, TMB) of the tumor, PD-L1 expression or CD8-T cell density[10,12,13,14,15], and to reduced egress of T cells from the bloodstream and influx into the tumor[16] Several of these immune evasive mechanisms have been evaluated in gliomas (gliomas for example have a low TMB and several studies showed that the antitumor immune response in HGGs is suppressed amongst others by enhanced PD-L1 expression17–22), most of these studies did not evaluate multiple immune parameters and/or did not evaluate potential differences between LGG and HGG. Since checkpoint inhibitors have limited effectivity in HGG patients, the near absence of TILs in LGG suggests that such effectivity may be even more limited in this tumor type
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