Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept

Abstract

Patients with glioblastoma multiforme (GBM) exhibit a deficient anti-tumor immune response. Both arms of the immune system were shown to be hampered in GBM, namely the local cellular immunity mediated by the Th 1 subset of helper T cells and the systemic humoral immunity mediated by the Th 2 subset of helper T cells. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, which may be attributed to its relative inaccessibility (the blood-brain barrier (BBB)), its poor immunogenicity, few characterized cancer antigens, or any of the many other immune mechanisms known to be hampered. Focused ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Mounting evidence suggests that in addition to thermal ablation, FUS induces mechanical acoustic cavitation and immunomodulation plays a key role in boosting the host anti-tumor immune responses. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The effect of FUS and microbubbles in disrupting the BBB and introducing antigens and drugs to the tumor milieu is discussed. The FUS-induced pro-inflammatory cytokines secretion and stress response, the FUS-induced change in the intra-tumoral immune-cells populations, the FUS-induced augmentation of dendritic cells activity, and the FUS-induced increased cytotoxic cells potency are all discussed. We next attempt at offering a conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy. In conclusion, it is increasingly apparent that no single treatment modality will triumph on GBM. The reviewed FUS-induced immunomodulation effects can be harnessed to current and developing immunotherapy approaches. Together, these may overcome GBM-induced immune-evasion and generate a clinically relevant anti-tumor immune response.

Can High Intensity Focused Ultrasound Facilitate Immunomodulation in Glioblastoma Multiforme?

“…It is the only noninvasive thermal technique that allows for real-time imaging of the treatment progress using MR-Thermometry [41] . Yet, the effects of FUS on the tissue are not merely thermal, shown to induce mechanical acoustic cavitation, carrying both mechanical and molecular implications and also modulate the host antitumor immune responses (table 2) [5] . We present a short report of research highlights capturing the essence of a paper we recently published [5] .…”

“…Yet, the effects of FUS on the tissue are not merely thermal, shown to induce mechanical acoustic cavitation, carrying both mechanical and molecular implications and also modulate the host antitumor immune responses (table 2) [5] . We present a short report of research highlights capturing the essence of a paper we recently published [5] . We will briefly discuss different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS.A potential conceptual synopsis of the two is presented.…”

“…A local inflammatory response should than be instigated and properly regulated. The multitude of immunosuppressive mechanisms (both active and passive) as well as immune-evasion techniques attributed to GBM cells are summarized in Table 1 [1,5] . These mechanisms independently, support the evolution of anergy and tolerance to the tumor.…”

“…Early reports of GBM patients who endured a post-operative surgical-site infection who surprisingly exhibited longer survival sparked an interest in many clinicians, suspecting an important role for the immune system both in disease progression as well as in tumor triumph. Since these initial pivotal observations, with developing techniques and widespread interest, multiple studies were put forward describing different molecular immunosuppressive mechanisms taking place in GBM cells and microenvironment, claiming these to be the dominant key events (table 1) [1,5] . Unfortunately, things are not as straightforward or simple, and both arms of the immune system are known to be hampered in GBM, as do many other anatomical barriers, micro-environmental conditions and features unique to tumors within the central nervous system, once termed as immune-privileged [27][28] .…”

“…macrophages), ƜCytotoxic (CD8+) T-lymphocytes, ƩSquamous Cell Carcinoma, ϦTumor infiltrating lymphocytes. + Based on Cohen-Inbar et al [5] developed mechanisms to evade or block its development at multiple steps (Table 1) [1,5] . Tumor associated target antigens must be sufficiently different from self-antigens, avoiding the development of immune-tolerance and anergy to self (and consequently to the tumor) on the one hand or the development of an auto-immune response on the other.…”