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. ABSTRACT: (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.