MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer.

BACKGROUND: Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance. METHODS: Mouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8+ T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment. RESULTS: Using preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8+ T cells. Activation of CD8+ T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R+CD11c+ MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME. CONCLUSION: Our findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor-host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.

A Comparison of Falls and Dizziness Handicap by Vestibular Diagnosis.

PURPOSE: There is a paucity of data that directly compares the falls rate and dizziness handicap of different vestibular diagnoses. The purpose of this study is to compare the falls rate and dizziness handicap of common vestibular diagnoses encountered among a cohort of vestibular patients at a single institution. METHOD: We conducted a retrospective cross-sectional study of patients evaluated for dizziness at a tertiary care center vestibular clinic between August 1, 2017, and March 19, 2019. Vestibular diagnosis, demographic variables, comorbidities, falls status, and Dizziness Handicap Inventory (DHI) were extracted from the medical record for analysis. Associations between vestibular diagnosis and falls history or DHI were evaluated using multivariate logistic and linear regression, respectively. RESULTS: A total of 283 patients met our inclusion criteria with the following diagnoses: benign paroxysmal positional vertigo (BPPV; n = 55), acoustic neuroma (n = 30), Ménière's disease (n = 28), multiple vestibular diagnoses (n = 15), vestibular migraine (n = 135), or vestibular neuritis (n = 20). After adjusting for age, sex, race, medications, and comorbidities, the odds of falling was 2.47 times greater (95% CI [1.08, 6.06], p = .039) and the DHI score was 11.66 points higher (95% CI [4.99, 18.33], p < .001) in those with vestibular migraine compared to those with BPPV. Other diagnoses were comparable to BPPV with respect to odds of falling and dizziness handicap. CONCLUSIONS: Patients with vestibular migraine may suffer an increased risk of falls and dizziness handicap compared to patients with BPPV. Our findings highlight the need for timely evaluation and treatment of all patients with vestibular disease.