Targeting abnormal immunomechanics in the glioblastoma microenvironment to improve therapeutic response

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ABSTRACT Newly diagnosed glioblastoma (GBM) patients have a dismal survival of less than 2 years despite aggressive currently available treatments. Immune checkpoint blockade (ICB), which has revolutionized the treatment of other solid tumors, fails to enhance survival in the majority of GBM patients. The immunosuppressive, hypoxic, and extracellular matrix (ECM)-rich tumor microenvironment (TME) may be largely responsible for this poor response. One of the largest and most immunosuppressive components of the GBM TME is the myeloid cell compartment, consisting mainly of resident microglia and infiltrating tumor-associated macrophages (TAMs). These myeloid cells exist along a spectrum of phenotypes and functions ranging from pro-tumor (pro-fibrotic, angiogenic, and immunosuppressive) to anti-tumor (immune-supporting), and can dictate response to therapy. Furthermore, the GBM TME harbors “solid stress” – a mechanical force originating from cells and ECM – that can compress blood vessels, induce hypoxia and immunosuppression, and hinder anti-tumor immunity and drug efficacy. Here it is proposed that “immunomechanics” between pro-tumor myeloid cells and solid stress are reciprocally regulated in GBM, further promoting the abnormal TME and mediating resistance to ICB. This mechanopathological feedback loop will be evaluated by i) confirming the ability of myeloid cells to exert solid stress, and ii) the reciprocal ability of solid stress to promote pro-tumor myeloid cell phenotype and function (Aim 1). Next, this reciprocal regulation will be interrupted (genetically and pharmacologically) in murine GBM models to i) establish the causal roles of myeloid cells and solid stress in mediating immunosuppression in the TME, and ii) propose translatable ways to overcome them (Aim 2). Finally, myeloid targeting approaches will be combined with ICB to enhance therapeutic outcome, and both physical (solid stress) and biological biomarkers of treatment response will be identified (Aim 3). The results of the proposed work in this K22 application will: i) facilitate my transition to independence, ii) lay the groundwork for a successful R01 application within 3 years, and iii) revealing novel and targetable biophysical mechanisms underlying tumor progression and treatment resistance.