Integrin avb8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy Graphical abstract Highlights d ITGB8 on CD4+/CD25+ T cells activates latent TGF-b, causing tumor immunosuppression d Anti-ITGB8 therapy elicits tumor regression and durable antitumor immunity d CD8+T cells are essential for anti-tumor activity of anti-ITGB8 d Anti-ITGB8 synergizes with multiple immunomodulators in multiple tumor types

The avb8 integrin is a key activator of transforming growth factor b (TGFb), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that avb8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against avb8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. avb8 is expressed on tumor cells in some of these models, but tumor cell expression of avb8 is not essential for the beneficial effects of ADWA-11 therapy. avb8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFb and are involved in tumor cell killing, including Granzyme B and Interferong. These findings solidify avb8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.

Importance: Vocal fold motion impairment (VFMI) due to neuronal injury is a known complication following thoracic aortic repair that can impair pulmonary toilet function and post-operative recovery. Objective: To demonstrate clinical outcomes of patients undergoing inpatient vocal fold medialization for VFMI after aortic surgery. Design: A 15-year retrospective chart review (2005-2019) of 259 patients with postoperative VFMI after thoracic aortic surgery registry was conducted. Data included demographics, surgery characteristics, laryngology exam, and postoperative clinical outcomes. Medialization procedures consisted of type 1 thyroplasty and injection laryngoplasty. Setting: Tertiary care hospital Participants: Two hundred and fifty-nine patients (median age 61, 71% male) with VFMI post-thoracic aortic repair met inclusion criteria; inpatient vocal fold medialization was performed for 203 (78%) patients. One hundred and twenty-six. (49%) received type 1 thyroplasty and 77 (30%) received injection laryngoplasty procedures at a median 7 days (IQR 5-8 days) from extubation. Main Outcomes: Primary study outcome measurements consisted of median LOS, median ICU LOS, complications intra- and postoperatively, and pulmonary complications (post-medialization bronchoscopies, pneumonia, tracheostomy, etc.). Results: Post-medialization bronchoscopy rates were significantly lower in the medialization (n = 11) versus the non-medialization group (n = 8) (5% vs 14%, P = .02) and significantly higher in the injection laryngoplasty group (n = 77) versus thyroplasty group (n = 126) (10% vs 2%, P = .02). Further analysis revealed no significant difference in overall LOS and pulmonary complications between the techniques. Conclusion: Inpatient thyroplasty and injection laryngoplasty are both effective vocal fold medialization techniques after extent I and II aortic repair. Thyroplasty may have a small pulmonary toilet advantage, as measured by need for post-medialization bronchoscopy, compared to injection laryngoplasty.

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