Role of anti-PD-1 antibody-Fc/FcR interaction on macrophages in inducing hyperprogressive disease in non-small cell lung cancer

Abstract

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis have made a breakthrough in the treatment of non-small cell lung cancer (NSCLC) [1]. However, a paradoxical boost in tumor growth was reported in a fraction of NSCLC patients after ICI administration; a novel pattern of cancer pro- gression defined “hyperprogression” (HP) [2]. Because the mechanism of HP onset is still unknown, aim of this study was to investigate this phenomenon. Among a cohort of NSCLC patients treated with ICI at Istituto Nazionale dei Tumori in Milan, cases with HP were identified according to clini- cal and radiological criteria. Among patients evaluable for clinical response (152/187), we identified 4 categories: Responders (21%), Stable Disease (27.7%), Progressors (25.7%) and HP (25.7%). Pre-treat- ment histological samples were evaluated by immunohistochemistry (IHC) for immune cell infiltrate. Tissue samples from all patients with HP showed tumor-infiltration by M2-like CD163+CD33+PD- L1+ clustered epithelioid macrophages. To validate these findings in preclinical models, we utilizedimmunocompromised mice that, lacking T-cells that may cloud the results, represent a suitable model to evaluate the role of macrophages in determining HP. Immunodeficient mice were injected with human NSCLC cells and patient-derived xenografts (PDXs), treated with anti-PD-1 antibody and tumor growth was assessed. Anti-PD-1 treated NSCLC-bearing mice showed HP-like tumor growth with dissemination to lung and iliac lymph node metastases, as well as an increase in tumor-associat- ed macrophages (TAMs) aggregating in fibrotic-like areas. Interestingly, in these in vivo models, HP- like growth, triggered by anti-PD-1 treatment, was abrogated by using anti-PD-1 F(ab)2-fragments. These results suggest that FcR engagement by ICI on TAMs may determine a functional reprogram- ming of these immune cells toward a more aggressive and pro-tumorigenic phenotype, eventually inducing HP.

This work was supported by AIRC and Ricerca Strategica Istituzionale (Istituto Nazionale dei Tumori di Milano)