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

Giuseppe Lo Russo, Massimo Moro, Michele Sommariva, Valeria Cancila, Mattia Boeri, Giovanni Centonze, Simona Ferro, Monica Ganzinelli, Patrizia Gasparini, Veronica Huber, Massimo Milione, Luca Porcu, Claudia Proto, Giancarlo Pruneri, Diego Signorelli, Sabina Sangaletti, Lucia Sfondrini, Chiara Storti, Elena Tassi, Alberto BardelliSilvia Marsoni, Valter Torri, Claudio Tripodo, Mario Paolo Colombo, Andrea Anichini, Licia Rivoltini, Andrea Balsari, Gabriella Sozzi, Marina Chiara Garassino

Research output: Contribution to journalArticle

Abstract

BACKGROUND: 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.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusE-pub ahead of print - Sep 11 2018

Fingerprint

Death Domain Receptors
Non-Small Cell Lung Carcinoma
Macrophages
Antibodies
Neoplasms
Lung Neoplasms
Growth
Fc Receptors
Heterografts
Flow Cytometry
T-Lymphocytes
Therapeutics

Cite this

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. / Lo Russo, Giuseppe; Moro, Massimo; Sommariva, Michele; Cancila, Valeria; Boeri, Mattia; Centonze, Giovanni; Ferro, Simona; Ganzinelli, Monica; Gasparini, Patrizia; Huber, Veronica; Milione, Massimo; Porcu, Luca; Proto, Claudia; Pruneri, Giancarlo; Signorelli, Diego; Sangaletti, Sabina; Sfondrini, Lucia; Storti, Chiara; Tassi, Elena; Bardelli, Alberto; Marsoni, Silvia; Torri, Valter; Tripodo, Claudio; Colombo, Mario Paolo; Anichini, Andrea; Rivoltini, Licia; Balsari, Andrea; Sozzi, Gabriella; Garassino, Marina Chiara.

In: Clinical Cancer Research, 11.09.2018.

Research output: Contribution to journalArticle

Lo Russo, G, Moro, M, Sommariva, M, Cancila, V, Boeri, M, Centonze, G, Ferro, S, Ganzinelli, M, Gasparini, P, Huber, V, Milione, M, Porcu, L, Proto, C, Pruneri, G, Signorelli, D, Sangaletti, S, Sfondrini, L, Storti, C, Tassi, E, Bardelli, A, Marsoni, S, Torri, V, Tripodo, C, Colombo, MP, Anichini, A, Rivoltini, L, Balsari, A, Sozzi, G & Garassino, MC 2018, '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', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-18-1390
Lo Russo, Giuseppe ; Moro, Massimo ; Sommariva, Michele ; Cancila, Valeria ; Boeri, Mattia ; Centonze, Giovanni ; Ferro, Simona ; Ganzinelli, Monica ; Gasparini, Patrizia ; Huber, Veronica ; Milione, Massimo ; Porcu, Luca ; Proto, Claudia ; Pruneri, Giancarlo ; Signorelli, Diego ; Sangaletti, Sabina ; Sfondrini, Lucia ; Storti, Chiara ; Tassi, Elena ; Bardelli, Alberto ; Marsoni, Silvia ; Torri, Valter ; Tripodo, Claudio ; Colombo, Mario Paolo ; Anichini, Andrea ; Rivoltini, Licia ; Balsari, Andrea ; Sozzi, Gabriella ; Garassino, Marina Chiara. / 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. In: Clinical Cancer Research. 2018.
@article{5b7eb221f58c4a9487e01ed3e0faaa00,
title = "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",
abstract = "BACKGROUND: 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.",
author = "{Lo Russo}, Giuseppe and Massimo Moro and Michele Sommariva and Valeria Cancila and Mattia Boeri and Giovanni Centonze and Simona Ferro and Monica Ganzinelli and Patrizia Gasparini and Veronica Huber and Massimo Milione and Luca Porcu and Claudia Proto and Giancarlo Pruneri and Diego Signorelli and Sabina Sangaletti and Lucia Sfondrini and Chiara Storti and Elena Tassi and Alberto Bardelli and Silvia Marsoni and Valter Torri and Claudio Tripodo and Colombo, {Mario Paolo} and Andrea Anichini and Licia Rivoltini and Andrea Balsari and Gabriella Sozzi and Garassino, {Marina Chiara}",
note = "{\circledC}2018 American Association for Cancer Research.",
year = "2018",
month = "9",
day = "11",
doi = "10.1158/1078-0432.CCR-18-1390",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",

}

TY - JOUR

T1 - 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

AU - Lo Russo, Giuseppe

AU - Moro, Massimo

AU - Sommariva, Michele

AU - Cancila, Valeria

AU - Boeri, Mattia

AU - Centonze, Giovanni

AU - Ferro, Simona

AU - Ganzinelli, Monica

AU - Gasparini, Patrizia

AU - Huber, Veronica

AU - Milione, Massimo

AU - Porcu, Luca

AU - Proto, Claudia

AU - Pruneri, Giancarlo

AU - Signorelli, Diego

AU - Sangaletti, Sabina

AU - Sfondrini, Lucia

AU - Storti, Chiara

AU - Tassi, Elena

AU - Bardelli, Alberto

AU - Marsoni, Silvia

AU - Torri, Valter

AU - Tripodo, Claudio

AU - Colombo, Mario Paolo

AU - Anichini, Andrea

AU - Rivoltini, Licia

AU - Balsari, Andrea

AU - Sozzi, Gabriella

AU - Garassino, Marina Chiara

N1 - ©2018 American Association for Cancer Research.

PY - 2018/9/11

Y1 - 2018/9/11

N2 - BACKGROUND: 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.

AB - BACKGROUND: 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.

U2 - 10.1158/1078-0432.CCR-18-1390

DO - 10.1158/1078-0432.CCR-18-1390

M3 - Article

C2 - 30206165

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -