Therapeutic Targeting of LIF Overcomes Macrophage-mediated Immunosuppression of the Local Tumor Microenvironment

Hallett, Robin M.; Bonfill-Teixidor, Ester; Iurlaro, Raffaella; Arias, Alexandra; Raman, Swetha; Bayliss, Peter; Egorova, Olga; Neva-Alejo, Almudena; McGray, AJ Robert; Lau, Esther; Bosch, Alexandre; Beilschmidt, Melissa; Maetzel, Dorothea; Fransson, Johan; Huber-Ruano, Isabel; Anido, Judit; Julien, Jean-Philippe; Giblin, Patricia; Seoane, Joan

doi:10.1158/1078-0432.ccr-21-1888

Therapeutic Targeting of LIF Overcomes Macrophage-mediated Immunosuppression of the Local Tumor Microenvironment

Journal Article · 28 November 2022 · Clinical Cancer Research

DOI:https://doi.org/10.1158/1078-0432.ccr-21-1888· OSTI ID:2423705

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Abstract Purpose:

Leukemia inhibitory factor (LIF) is a multifunctional cytokine with numerous reported roles in cancer and is thought to drive tumor development and progression. Characterization of LIF and clinical-stage LIF inhibitors would increase our understanding of LIF as a therapeutic target.

Experimental Design:

We first tested the association of LIF expression with transcript signatures representing multiple processes regulating tumor development and progression. Next, we developed MSC-1, a high-affinity therapeutic antibody that potently inhibits LIF signaling and tested it in immune competent animal models of cancer.

Results:

LIF was associated with signatures of tumor-associated macrophages (TAM) across 7,769 tumor samples spanning 22 solid tumor indications. In human tumors, LIF receptor was highly expressed within the macrophage compartment and LIF treatment drove macrophages to acquire immunosuppressive capacity. MSC-1 potently inhibited LIF signaling by binding an epitope that overlaps with the gp130 receptor binding site on LIF. MSC-1 showed monotherapy efficacy in vivo and drove TAMs to acquire antitumor and proinflammatory function in syngeneic colon cancer mouse models. Combining MSC-1 with anti-PD1 leads to strong antitumor response and a long-term tumor-free survival in a significant proportion of treated mice.

Conclusions:

Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy.

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC02-06CH11357

OSTI ID:: 2423705

Journal Information:: Clinical Cancer Research, Journal Name: Clinical Cancer Research Journal Issue: 4 Vol. 29; ISSN 1078-0432

Publisher:: American Association for Cancer Research

Country of Publication:: United States

Language:: English

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