Is impaired response to PD-1 blockers of high serum PD-1 patients related to immune complexes?
Authors: E. Daveri, E. Luison, V. Vallacchi, B. Vergani, B.E. Leone, M.C. Garassino, M. Figini, L. Rivoltini
Journal: Annals of Oncology (2021)

Ugurel et al.1Ugurel S. Schadendorf D. Horny K. et al.Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma.Ann Oncol. 2020; 31: 144-152Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar reported in this journal that high serum programmed cell death protein 1 (sPD-1) levels were associated with lower clinical benefit in melanoma patients treated with PD-1 blockers, suggesting that sPD-1 binding to anti-PD-1 monoclonal antibody (mAb) might reduce the bioavailability of this therapeutic agent. However, the lack of obvious dose dependency in the clinical efficacy of PD-1 blockers does not entirely support the hypothesis that sPD-1-mediated loss of some antigenic binding sites might actually interfere with the antitumor activity of anti-PD-1 mAbs. Here we would like to raise the possibility that the process could also stem from the in vivo formation of sPD-1/anti-PD-1 mAb immune complexes (PD-1-IC). Indeed, as the immune complexes are stable antigen-antibody structures displaying distinctive regulatory functions through the interaction of mAb-fragment crystallizable (Fc) region with Fcγ-receptor-(FcγR)-expressing cells,2Dahan R. Sega E. Engelhardt J. Selby M. Korman A.J. Ravetch J.V. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis.Cancer Cell. 2015; 28: 285-295Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar it is conceivable that PD-1-IC could decrease clinical benefit by inducing unwanted immunological effects via Fc/FcγR bonds. We report here that PD-1 nivolumab IC (nivo-IC) can bind in vitro to all human FcγRs, including FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b, FcγRIIIa/CD16a and FcγRIIIb/CD16b, albeit with different kinetics. Rather, when nivo-IC is depleted of the Fc portion [F(ab)2 nivo-IC], there is no interaction with any of the tested FcγRs (Figure 1A). To assess if the nivo-IC binding also occurred at the immune cell level leading to any functional consequences, we focused on human macrophages (hMϕ), which are FcγRs+ elements (Figure 1B), highly represented in the tumor microenvironment.3Gubin M.M. Esaulova E. Ward J.P. et al.High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy.Cell. 2018; 175: 1014-1030.e19Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar,4Lo Russo G. Moro M. Sommariva M. et al.Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.Clin Cancer Res. 2019; 25: 989-999Crossref PubMed Scopus (228) Google Scholar As depicted in Figure 1C, hMϕ interact with nivo-IC in an fragment crystallizable receptor-dependent manner and rapidly internalize the complex as shown by confocal microscopy (Figure 1D). Most importantly, according to transcriptional (Figure 1E) and released cytokine analyses (Figure 1F), nivo-IC binding and endocytosis impair hMϕ polarization towards antitumor classically activated macrophages (M1) cells and switch them to a protumorigenic alternatively activated macrophages (M2) profile. Although based only on in vitro data, this first report on the immunomodulating properties of PD-1-IC may generate new hypotheses about the mechanisms of resistance to PD-1 blockers (Figure 1G). Indeed, the presence of sPD-1 in cancer patients' blood,1Ugurel S. Schadendorf D. Horny K. et al.Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma.Ann Oncol. 2020; 31: 144-152Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar the remarkable affinity of anti-PD-1 mAbs for their antigenic determinants and the abundance of FcγR-expressing myeloid cells in the tumor microenvironment5Liu R. Oldham R.J. Teal E. Beers S.A. Cragg M.S. Fc-engineering for modulated effector functions-improving antibodies for cancer treatment.Antibodies (Basel). 2020; 9: 64Crossref Scopus (30) Google Scholar make the process described here likely to occur in vivo as well. If so, PD-1-IC could contribute to favor macrophage skewing toward protumorigenic cells and possibly hinder the cancer-associated myeloid cell reprogramming recently described to precede tumor regression by PD-1 blockade.3Gubin M.M. Esaulova E. Ward J.P. et al.High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy.Cell. 2018; 175: 1014-1030.e19Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The findings depicted here build on our previous data indicating that M2-Mϕ tumor infiltrate correlates with poor clinical outcome in non-small-cell lung cancer (NSCLC) patients treated with PD-1 blockers and that F(ab)2-anti-PD1 mAb loses its pro-tumor effects in preclinical models.4Lo Russo G. Moro M. Sommariva M. et al.Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade.Clin Cancer Res. 2019; 25: 989-999Crossref PubMed Scopus (228) Google Scholar Above all, our results suggest that tools of PD-1 blockade possibly avoiding Fc/FcγR interactions, such as mAbs null for fragment crystallizable receptor-binding5Liu R. Oldham R.J. Teal E. Beers S.A. Cragg M.S. Fc-engineering for modulated effector functions-improving antibodies for cancer treatment.Antibodies (Basel). 2020; 9: 64Crossref Scopus (30) Google Scholar or tools for Ab-independent blockade, might contribute to potentiate clinical benefit of anti-PD-1 agents. Detecting PD-1-IC is technically challenging, as most anti-PD-1 mAbs recognize the active epitope seen by PD-1 blockers. Nevertheless, a test quantifying plasma PD-1-IC also promises to provide a new resistance biomarker to implement the predictive value of sPD-1. The authors thank Paola Squarcina, Agata Cova, Simona Frigerio and Silvia Brich for their technical support and Veronica Huber for scientific advice. All authors have read and agreed to the submitted version of the manuscript. This work was supported by 5x1000 Funds 2014, Italian Ministry of Health (MoH) Institutional grant from Fondazione IRCCS , Istituto Nazionale dei Tumori di Milano , ‘Identification of patients with lack of response or detrimental effect to immune-checkpoint inhibitors targeting PD-1/PD-L1 axis’ [grant number BRI2017 ] to M.C.G. and PRECIOUS Project-Horizon 2020 [grant number 686089 ] to L.R.