Immune Monitoring in Melanoma and Urothelial Cancer Patients Treated with Anti-PD-1 Immunotherapy and SBRT Discloses Tumor Specific Immune Signatures

Simple Summary Currently available biomarkers for response to checkpoint inhibitors are incomplete and predominantly focus on tumor tissue analysis e.g., tumor mutational burden, programmed cell death-ligand 1 (PD-L1) expression. Biomarkers in peripheral blood would allow a more dynamic monitoring and could offer a way for sequential adaptation of treatment strategy. We conducted an in-depth analysis of baseline and on-treatment systemic immune features in a cohort of stage III/IV melanoma and stage IV urothelial cancer (UC) patients treated with anti-programmed cell death-1 (anti-PD-1) therapy combined with stereotactic body radiotherapy (SBRT) in a similar regimen/schedule. Baseline immunity was clearly different between these two cohorts, indicating a less active immune landscape in UC patients. This study also detected signatures of proliferation in the CD8(+) T-cell compartment pre-treatment and early after anti-PD-1 initiation that were positively correlated with clinical outcome in both tumor types. In addition our data support the biological relevance of PD-1/PD-L1 expression on circulating immune cell subsets, especially in melanoma. (1) Background: Blockade of the PD-1/PD-L1 pathway has revolutionized the oncology field in the last decade. However, the proportion of patients experiencing a durable response is still limited. In the current study, we performed an extensive immune monitoring in patients with stage III/IV melanoma and stage IV UC who received anti-PD-1 immunotherapy with SBRT. (2) Methods: In total 145 blood samples from 38 patients, collected at fixed time points before and during treatment, were phenotyped via high-parameter flow cytometry, luminex assay and UPLC-MS/MS. (3) Results: Baseline systemic immunity in melanoma and UC patients was different with a more prominent myeloid compartment and a higher neutrophil to lymphocyte ratio in UC. Proliferation (Ki67(+)) of CD8(+) T-cells and of the PD-1(+)/PD-L1(+) CD8(+) subset at baseline correlated with progression free survival in melanoma. In contrast a higher frequency of PD-1/PD-L1 expressing non-proliferating (Ki67(-)) CD8(+) and CD4(+) T-cells before treatment was associated with worse outcome in melanoma. In UC, the expansion of Ki67(+) CD8(+) T-cells and of the PD-L1(+) subset relative to tumor burden correlated with clinical outcome. (4) Conclusion: This study reveals a clearly different immune landscape in melanoma and UC at baseline, which may impact immunotherapy response. Signatures of proliferation in the CD8(+) T-cell compartment prior to and early after anti-PD-1 initiation were positively correlated with clinical outcome in both cohorts. PD-1/PD-L1 expression on circulating immune cell subsets seems of clinical relevance in the melanoma cohort.