Background: Promising rates of response to ICI have been observed in patients with OSCC. This is phase I/II study with focus on biological changes observed in sequential tissue acquisition. Methods: Eligibility criteria: Resectable OSCC stage IV Description of each treatment arm: Arm A: durvalumab (1500 mg) on day -14 and 6 cycles adjuvant Arm B: durvalumab (1500 mg) and tremelimumab (75 mg) combination on day -14 and 6 cycles adjuvant Primary endpoint: Biological response in tumor tissue by means of difference in CD8+ lymfocyte infiltration density (TIL) and % remaining viable tumor cells. Secondary endpoints: Recist v1.1 OS PBMC and plasma analysis scRNA-seq Statement of study design: open-label, prospective stratified, phase I/II study. Results: No ICI related toxicity interfered with surgery. 50 % of patients presented with at least 1 severe AE. There was no difference between both arms. 2 year OS is 64% in arm A and 80% in arm B. Both arms show a significant increase (p = 0,01) in TILs. We observed a significant decrease in viable tumor cells (p < 0,01). No objective pathological response with > 50% decrease of viable tumor cells was observed. T-cell expansion varied although a positive correlation between T-cell expansion and radiologic tumor shrinkage was demonstrated (p < 0.001). T-cell expansion was tumor-specific (p = 0.749). Differential gene expression analysis comparing expanding T-cells in tumors observed increased expression of effector/activation markers and immune cell homing in expanding T-cells, but reduced expression of naïve and immune regulatory markers. By also profiling tumor-draining lymph nodes, we observe that the addition of aCTLA4 affects the lymph nodes and primes CD4+ naïve T-cells, triggering their expansion. Systemically PD-1 expression in both CD4+ and CD8+ T cells is increased together with an upregulation of activation markers after ICI. 2 baseline plasma factors with predictive capacity for clonotype response were identified: baseline LAG-3 and B7.2(CD86). Conclusions: A 14-day window may be considered ethically sound, it might not provide sufficient time for evaluating pathological response. It is both safe and feasible to use neoadjuvant ICI treatment in OSCC. While the initial toxicity is low and does not interfere with standard of care surgical procedures, adjuvant treatment may result in higher toxicity. Response to ICI is not dichotomic but rather a continuous variable which we represent here as clonotype expansion. A positive correlation was demonstrated between T-cell expansion and radiologic tumor shrinkage after one cycle of ICB. T-cell expansion was tumor-specific and gene expression analysis observed increased expression of activation markers here further supporting this as a surrogate marker. Combination therapy facilitates expansion of both CD4+ and CD8+ T-cells versus just CD8+ T-cells with aPD-L1 alone. Clinical trial information: NCT03784066.