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RESEARCH PRODUCT
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
Giovanni CentonzeLicia RivoltiniElena TassiGiancarlo PruneriMassimo MilioneClaudia ProtoGabriella SozziMario P. ColomboMarina Chiara GarassinoPatrizia GaspariniAndrea BalsariSimona FerroLuca PorcuSilvia MarsoniDiego SignorelliAndrea AnichiniMonica GanzinelliChiara StortiValter TorriValeria CancilaGiuseppe Lo RussoMassimo MoroMattia BoeriMichele SommarivaLucia SfondriniVeronica HuberAlberto BardelliSabina SangalettiClaudio Tripodosubject
0301 basic medicineMaleCancer ResearchMyeloidLung NeoplasmsCD33Programmed Cell Death 1 ReceptorFc receptorMice NudeMice SCIDReceptors Fcnon-small cell lung cancer Hyperprogression immune checkpoint inhibitors.B7-H1 AntigenArticle03 medical and health sciences0302 clinical medicineImmunophenotypingAntineoplastic Agents ImmunologicalPD-L1Carcinoma Non-Small-Cell LungCell Line TumormedicineAnimalsHumansLung cancerAntibodies Blockingbiologybusiness.industryMacrophagesmedicine.diseaseXenograft Model Antitumor Assays3. Good healthImmunoglobulin Fc FragmentsTumor Burden030104 developmental biologymedicine.anatomical_structureNivolumabOncology030220 oncology & carcinogenesisbiology.proteinCancer researchImmunohistochemistryFemaleAntibodybusinessdescription
Abstract Purpose: Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological mechanisms associated with HP have been identified. Experimental Design: Among 187 patients with non–small cell lung cancer (NSCLC) treated with ICI at our institute, cases with HP were identified according to clinical and radiologic criteria. Baseline histologic samples from patients treated with ICI were evaluated by IHC for myeloid and lymphoid markers. T-cell–deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDX) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC. Results: Among 187 patients, 152 were evaluable for clinical response. We identified four categories: 32 cases were defined as responders (21%), 42 patients with stable disease (27.7%), 39 cases were defined as progressors (25.7%), and 39 patients with HP (25.7%). Pretreatment tissue samples from all patients with HP showed tumor infiltration by M2-like CD163+CD33+PD-L1+ clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti–PD-1 but not anti–PD-1 F(ab)2 fragments. Conclusions: These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP. See related commentary by Knorr and Ravetch, p. 904
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-01-01 | Clinical Cancer Research |