Purpose: Tumor antigen–specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)–mediated cytotoxicity. However, the role of CD8+ CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. Experimental Design: FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)–specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry. Results: FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR853–861–specific CD8+ T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR+ tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ–dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (TH1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell–induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. Conclusion: Cetuximab-activated NK cells promote DC maturation and CD8+ T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through “NK–DC cross-talk.” FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK–DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response. Clin Cancer Res; 19(7); 1858–72. ©2013 AACR.

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4⁺FOXP3⁺ intratumoral Treg expressing CTLA-4, CD39, and TGFβ. These Treg suppressed cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4⁺FOXP3⁺ Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFβ and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4⁺ Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity. Cancer Res; 75(11); 2200–10. ©2015 AACR.

Objective: To evaluate the clinical applications and limitations of chat generative pretrained transformer (ChatGPT) in otolaryngology.Study Design: Cross‐sectional survey.Setting: Tertiary academic center.Methods: ChatGPT 4.0 was queried for diagnoses and management plans for 20 physician‐written clinical vignettes in otolaryngology. Attending physicians were then asked to rate the difficulty of the clinical vignettes and agreement with the differential diagnoses and management plans of ChatGPT responses on a 5‐point Likert scale. Summary statistics were calculated. Univariate ordinal regression was then performed between vignette difficulty and quality of the diagnoses and management plans.Results: Eleven attending physicians completed the survey (61% response rate). Overall, vignettes were rated as very easy to neutral difficulty (range of median score: 1.00‐4.00; overall median 2.00). There was a high agreement with the differential diagnosis provided by ChatGPT (range of median score: 3.00‐5.00; overall median: 5.00). There was also high agreement with treatment plans (range of median score: 3.00‐5.00; overall median: 5.00). There was no association between vignette difficulty and agreement with differential diagnosis or treatment. Lower diagnosis scores had greater odds of having lower treatment scores.Conclusion: Generative artificial intelligence models like ChatGPT are being rapidly adopted in medicine. Performance with curated, easy‐to‐moderate difficulty otolaryngology scenarios indicate high agreement with physicians for diagnosis and management. However, a decreased quality in diagnosis is associated with decreased quality in management. Further research is necessary on ChatGPT's ability to handle unstructured clinical information.