Background: Preclinical models suggest that PARP inhibitor-induced DNA damage can promote immune priming through a range of mechanisms including STING pathway activation. PARP inhibition also leads to adaptive upregulation of PD-L1 expression in preclinical models. To understand the distinct effects that different forms of DDR defects may have on tumor immunogenicity we decided to integrate genomic profiling with gene expression profiling and immunohistochemistry (IHC)/fluorescent assessments of PD-L1 expression, CD8 T-cell infiltration, and broad immune infiltrate, in order to define the overlap between DDR and immune-related biomarker groups and to build a deeper understanding of how DNA damage interfaces with antitumor immunity. Methods: 39 patients were enrolled in OPHELIA phase II trial in which pts were randomized 3:3:3:1 to Cisplatin (C) 60 mg/m2 on d1 followed by Olaparib (O) 75mg d 1-5 (Arm A), O 300 mg bid for 21-28 days (Arm B), no treatment (ARM C) or D 1500 mg on d1 followed by O 600 mg daily for 21-28 days (Arm D). PD-L1, STING, Ki67 and γ-H2AX were assessed using quantitative immunofluorescence (QIF). The GeneXpert (GX) closed system real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used for quantitative assessment of CD274 (PD-L1), PDCD1LG2 (PD-L2), CD8A, and IRF1 multiplex mRNA panel in pre- and post-treatment samples. Results: Ki67 was decreased in 23 out of 29 (79.3%) available samples when assessed by QIF; 13 / 23 had a decrease of at least 25%. Δγ-H2AX did not differ among treatment groups. A significant increase was observed in PD-L1 and PD-L2 mRNA levels after treatment with D-O (p = 0.023 and p = 0.016, respectively). An increase trend in posttreatment CD8A mRNA was observed in 23 out of 29 cases in the three treatment arms (p = 0.21, ARM A; p = 0.082, ARM B; p = 0.16, ARM D). IRF1 mRNA and STING protein levels were not upregulated after olaparib- based treatment in the available paired treatment samples. Conclusions: This window study demonstrated a significant upregulation of PD-L1 mRNA, corresponding to our previous data of increased Combined Positive Score (CPS) in the D-O arm post-treatment. Our findings suggest that addition of D to O leads to PD-L1 upregulation. Dual blockade of PARP and PD-1 can boost immune response and antitumor activity in HNSCC. Clinical trial information: NCT02882308