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Non–small cell lung cancer: antibody–Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease subsequent to PD-1/PD-L1 blockade


Hyperprogression, 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 hyperprogression have been identified.

Among 187 patients with non–small cell lung cancer ( NSCLC ) treated with immune checkpoint inhibitors at Fondazione IRCCS Istituto Nazionale dei Tumori ( Milan, Italy ), cases with hyperprogression were identified according to clinical and radiologic criteria.
Baseline histologic samples from patients treated with immune checkpoint inhibitors were evaluated by immunohistochemistry 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 immunohistochemistry.

Among 187 patients, 152 were evaluable for clinical response.

Investigators 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 hyperprogression ( 25.7% ).

Pretreatment tissue samples from all patients with hyperprogression have shown 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.

In conclusion, these results suggest a crucial role of tumor-associated macrophages reprogramming, upon Fc receptor engagement by immune checkpoint inhibitors, eventually inducing hyperprogression and provide clues on a distinctive immunophenotype potentially able to predict hyperprogression. ( Xagena )

Lo Russo G et al, Clinical Cancer Research, 10.1158/1078-0432.CCR-18-1390 2019

XagenaMedicine_2019



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