Auto-antibodies neutralizing type-I IFNs (AAN-I-IFN) were recently uncovered as enriched in critically ill COVID-19 patients, where they act as major negative regulators of anti-viral immune response. IFN-I also play a central role in the regulation of anti-tumor immune response, however, the presence and functional impact of AAN-I-IFN has never been explored in tumoral context. Here, we evaluated the presence of circulating AAN-I-IFN in a large pan-cancer patient cohort and evaluated their functional impact on patient outcome.

We evaluated the frequency and neutralizing activity of circulating AAN-I-IFN in a cohort of 1,966 cancer patients across several tumor types (melanoma, n=453; glioma, n=270; colon cancer, n=267; diffuse large B-cell lymphoma, n=249; lung cancer, n=238; follicular lymphoma, n=107; Hodgkin lymphoma, n=96, stomach cancer, n=90; breast cancer, n=16; others, n=180) by ELISA and using an ISRE-luciferase neutralization assay in the presence of varying concentrations of IFN-Is. Response to immune checkpoint blockade (ICB) was analyzed according to relapse-free survival of patients in n=270 melanoma patients. For mechanistic analyses, mice were inoculated with Yumm1.7 ICB-resistant melanoma cell line and immunized to generate AAN-I-IFN prior treatment with anti-PD1. Spatial transcriptomic (Xenium, Human 5k panel) was performed on FFPE tumor samples from AAN-I-IFN-positive patients and -negative matched controls.

We found an overall frequency of 0.61% of cancer patients positive for AAN-I-IFN, with similar frequencies across all cancer types. Consistent with previous observations in healthy individuals, AAN-I-IFN were significantly increased across ageing in cancer patients. No differences in the frequency of AAN-I-IFN was observed between cancer patients and healthy subjects (0.617% vs 0.963%, p-value=0.23). Regarding the impact of AAN-I-IFN on melanoma patients’ clinical response to ICB, we observed a significant enrichment of long-duration responses to ICB (>4 years) in patients with AAN-I-IFN. In vivo experiments using an ICB-resistant melanoma model confirmed that only AAN-I-IFN-positive mice showed strong reduction of tumor growth in response to ICB. Finally, spatial transcriptomic analysis revealed a significant enrichment of tumor-infiltrating effector memory CD8⁺ T-cells in patients with AAN-I-IFN as compared to negative matched controls.

Together, our results highlight that AAN-I-IFN potentiate ICB efficacy in melanoma patients, and uncover a previously underestimated role of auto-antibodies directed against cytokines in the regulation of anti-tumor immune response in cancer patients.