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

Abstract

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. Fundings: AIRC, MIUR and Sapienza University of Rome.

Rheumatoid Factor: A Novel Determiner in Cancer History

“…In accordance with these observations, in a recent work, we showed that IgM-RF is not able to prevent the engagement between the drug Nivolumab (an IgG4 monoclonal antibody) and its target receptor PD-1 on T-cells [ 51 ]. Instead, IgM-RF is able to bind preferentially naïve and central memory CD4 + and CD8 + T-cells, leading to an impaired in vitro migration of these T-cell subsets in response to the CCL19 cytokine [ 51 , 61 ]. Moreover, RF-positive NSCLC patients showed a significant reduction of the CD137 + T-cells, which identify the tumor-specific effector T-cell population [ 71 ].…”

“…The presence of RFs can be detected in the blood of 10–20% of cancer patients [ 50 ], reaching 26% in non-small lung cancer (NSCLC) patients [ 51 ]. The higher prevalence of RF positivity in cancer patients compared to the general healthy population can be surely explained by the older age of subjects affected by cancer, since RFs production is associated with aging; however, it could also suggest a possible association between RF positivity and cancer.…”

“…Finally, a retrospective study conducted in our laboratory brought clear evidence of how the IgM–RF positivity is a strong predictive factor for the development of NSCLC patients’ early progression in response to the treatment with anti-PD-1 immune checkpoint inhibitors (ICIs) [ 51 , 61 ]. IgM-RF also correlates with a negative prognosis in terms of both overall survival (OS) and progression-free survival (PFS) in metastatic NSCLC patients in treatment with an anti-PD-1 ICI, with the worst outcome shown by patients with titers greater than 50 IU/mL [ 51 , 61 ].…”

“…Moreover, RF-positive NSCLC patients showed a significant reduction of the CD137 + T-cells, which identify the tumor-specific effector T-cell population [ 71 ]. This suggests that the dysfunctional recirculation of naïve and central memory T-cells due to the presence of IgM-RF can lead to an impaired expansion of the tumor-directed effector T-cell population, consequently resulting in the failure of the anti-PD-1 treatments that relies on tumor-specific effector T-cells in order to be effective [ 51 ] ( Figure 1 ).…”

CD137+ T-Cells: Protagonists of the Immunotherapy Revolution

“…In 2020, for the first time we provided evidence about the importance of CD137 + T-cells in determining the outcome of metastatic non-small cells lung cancer (NSCLC) patients undergoing immunotherapies [67,68]. Patients that were positive for the autoantibody IgM-Rheumatoid Factor (IgM-RF) showed indeed a reduced frequency of CD137 + T-cells in peripheral blood and an increased tendency to develop an early progression, in addition to a markedly reduced progression-free survival (PFS) and overall survival (OS) after the anti-PD-1 treatment [68].…”