IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137 + T-cells

Background: ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137+T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies. Methods: Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated. Findings: IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naïve and central memory T-cells and a significant reduction of CD137+ anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137+T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine. Interpretation: In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137+ T-cells population that may cause a non-effectiveness of these T-cells targeting drugs.