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 language | English |
|---|---|
| Journal | Clinical Cancer Research |
| DOIs | |
| Publication status | E-pub ahead of print - Sep 11 2018 |
Fingerprint
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 journal › Article
}
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 -