Immunotherapy in gliomas: Are we reckoning without the innate immunity?

Abstract

Innate immunity plays a central role in neoplasms, including those affecting the central nervous system (CNS). Nowadays, tumors classification, especially that regarding gliomas, is based on molecular features such as mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Therapy, in most cases, is based on surgery, radiotherapy, and pharmacological treatment with chemotherapeutic agents such as temozolomide. However, the results of the treatments, after many decades, are not completely satisfactory. There is a class of drugs, used to treat cancer, which modulates immune response; in this class, the immune checkpoint inhibitors and vaccines play a prominent role. These drugs were evaluated for the treatment of gliomas, but they exhibited a poor outcome in clinical trials. Those scarce results could be due to the response of tumor-associated macrophage that creates imbalances between innate and adaptive immunity and changes in blood-brain barrier properties. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role for innate immunity in the failure of immunotherapies against brain tumors.

Keywords: glioblastoma; immunotherapyinnate immunity; macrophage polarization; neoplasm staging; tumor-associated macrophages.

Figure 1.

Mechanism of action of immunotherapic drugs: (a) tumor cells (TC) express the transmembrane protein, programmed death ligand-1 (PD-L1) or PD-L2. The binding of PD-L1 or PD-L2 to its receptor PD-1, found on T cells, transmits a signal that inhibits the T-cell receptor (TCR)-mediated activation and proliferation of the T cells. This signaling mechanism allows the evasion from anti-tumor response and (b) the FDA-approved immunotherapic drugs durvalumab, atezolizumab, and avelumab consist of human monoclonal IgG1 directed against PD-L1 or PD-L2. Pembrolizumab and nivolumab are humanized mouse IgG4 monoclonals that target PD-1. These kinds of drugs are called immune checkpoint inhibitors (ICIs).

Figure 2.

Direct and indirect action of TAMs and hypoxia-driven immunosuppressive dynamics in glioma microenvironment: (a) cytotoxic lymphocytes (CTL) could be led on to apoptosis through the interaction FasL/FasR expressed on TAMs and CTL, respectively, (b) alternative polarized TAM by secreting chemokine such as CCL2 are able to recruit T_reg cells inside the tumor microenvironment and these suppressor T cells inhibit CTL, and (c) hypoxia can induce several cell types to secrete vascular endothelial growth factor (VEGF) among which are tumor cells (TC), tumor-associated macrophages (TAM), and mast cells (MC). VEGF, in turn, can induce the expression of membrane-anchored Fas ligand (FasL) on the vascular endothelium during angiogenesis. The interaction between FasL and Fas receptor (FasR) or CD95 drag CTL toward the apoptotic program.

Figure 3.

Potential mechanisms contributing to immunotherapy and tumor vaccination failure (a) programmed death ligand 1 and/or 2 (PD-L1/PD-L2) are commonly expressed on the surface of dendritic cells or macrophages. Tumor-associated macrophages (TAM) can become the prevalent cell population on glioma tissue. This leads to a heavy reduction of the immunotherapy drugs that could target tumor cell inhibitory interactions with cytotoxic T cells (CTLs) and (b) cooperative action between tumor cells (TC) and tumor-associated macrophages (TAM) to tumor escape from immune surveillance. Activated cytotoxic T lymphocyte (CTL) could be inhibited by tumor cells through a repressive signaling, triggered by PD-1/PD-L1 interaction. TAMs can concur to it, routing the same immunosuppressive signal by the same receptor/ligand interaction and, additionally, can reinforce it with a supplementary inhibitory signal to specific CTL for tumor antigens. This last signal is channeled via binding of CD80 and/or CD85, expressed on TAMs surface, with CTLA-4 (cytotoxic T lymphocyte antigen 4) expressed on CTL surface.