Background: This study was proposed to elucidate the impact of combining anti-platelet therapy with an immune checkpoint inhibitor (ICI) in altering the CD8⁺ T cell function in patients with head and neck squamous cell carcinoma (HNSCC). With a total enrollment of 15 of out an expected 20 patients, this report characterizes the findings thus far from the ongoing study. Methods: This crossover trial consisted of two different treatment regimens for two groups. Regimen A involved treatment with a PD-1 inhibitor pembrolizumab (200 mg iv over 30 min) every 3 weeks in combination of daily aspirin (81 mg orally) and clopidogrel (75 mg orally) for a total of 6 weeks. Regimen B involved pembrolizumab monotherapy (200 mg iv over 30 min) every 3 weeks for two cycles. Thus far, 15 patients with recurrent or metastatic HNSCC were randomized into the two groups, with Group 1 receiving Regimen A followed by Regimen B, while Group 2 received Regimen B followed by Regimen A. In addition to clinical endpoint, in depth analysis of the peripheral blood mononuclear cells (PBMCs) was also implemented using samples obtained prior to treatment, in between regimens, and at the end of treatment. These samples were then analyzed using a spectral flow cytometer panel specific for human CD8⁺ T cells. Given the 75 percent accrual, we performed analysis with the obtained clinical samples and data. Results: Of the 15 patients enrolled into the study, 14 remained on study and completed the trial till endpoint. All 14 patients presented with no overtly significant adverse events (AEs). In terms of clinical response, we observed in Group 1 patients (n=7) a total of 1 CR (complete response), 1 PR (partial response), 2 SD (stable disease), and 3 PD (progressive disease), while Group 2 (n=7) presented with 2 PR, 2 SD, and 3 PD. Spectral flow analysis performed on Group 1 patient samples revealed an increase in the Ki67⁺PD1⁺ proliferative subset post combination treatment (p value < 0.05, paired Student’s t-test). This finding indicates a potential increase in proliferation among CD8⁺ T cells after antigen stimulation that may pertain to the combination of anti-PD-1 and anti-platelet therapy. In addition, a higher frequency of Ki67⁺TIGIT⁺ CD8⁺ population (p value < 0.05, paired Student’s t-test) was also observed after combination therapy compared to pre-treatment; however, this level was not sustained after combination therapy was ceased, implying that ongoing anti-platelet therapy may be necessary for augmenting ICI. Conclusions: Combination of anti-PD1 and anti-platelet therapy demonstrates potential for remodeling the immune compartment pertaining to CD8⁺ T cells without resulting in overt toxicity. Further analysis of the effects of this combination regimen will be essential to better characterize tumor specific impact. Clinical trial information: NCT03245489.