Improving immunotherapy responses by dual inhibition of macrophage migration inhibitory factor and PD-1
Thuy T. Tran, Gabriela Athziri Sánchez-Zuno, Lais Osmani, Jasmine Caulfield, Caroline Naomi Valdez, Marta Piecychna, Lin Leng, Michelle E. Armstrong, Seamas C. Donnelly, Carlo B. Bifulco, Terri Clister, Rajan P. Kulkarni, Lin Zhang, Mario Sznol, Lucia Jilaveanu, Harriet M. Kluger, Insoo Kang, Richard Bucala
Thuy T. Tran, Gabriela Athziri Sánchez-Zuno, Lais Osmani, Jasmine Caulfield, Caroline Naomi Valdez, Marta Piecychna, Lin Leng, Michelle E. Armstrong, Seamas C. Donnelly, Carlo B. Bifulco, Terri Clister, Rajan P. Kulkarni, Lin Zhang, Mario Sznol, Lucia Jilaveanu, Harriet M. Kluger, Insoo Kang, Richard Bucala
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Research Article Immunology Oncology

Improving immunotherapy responses by dual inhibition of macrophage migration inhibitory factor and PD-1

Abstract

Macrophage migration inhibitory factor (MIF) is an upstream regulatory cytokine that is associated with advanced disease and poor outcomes in multiple cancer types, including melanoma. We investigated whether anti-MIF therapy could enhance the antitumor effects of the immune checkpoint inhibitor anti–programmed cell death 1 (anti–PD-1) in 2 murine tumor models. The therapeutic efficacy of anti-MIF, alone or combined with anti–PD-1, was tested in the YUMMER1.7 melanoma and MC38 colorectal cancer models. Tumor growth and survival were assessed in untreated Mif-knockout (KO) and low-expression human MIF allele (CATT5) mice and compared with wild-type (WT) or high-expression MIF allele (CATT7) mice. Tumor-bearing animals underwent cytokine profiling, tumor immunohistochemistry, flow cytometry, and scRNA-Seq. We also correlated functional variant MIF alleles with melanoma incidence and progression in patients. Our results showed that combined anti-MIF and anti–PD-1 significantly reduced tumor growth, improved survival, and promoted tumor regression, accompanied by enhanced TH1 cytokine levels, increased macrophage activation–related cytokines, and increased type 1 conventional dendritic cells. scRNA-Seq analysis revealed an expansion of intratumor Cd74/C1q/Aif1-expressing macrophages, which exhibited an antitumor phenotype, in response to anti-MIF therapy. MIF-KO and CATT5 mice exhibited reduced tumor burdens compared with WT or CATT7 mice alone and in the presence of anti–PD-1. In patients with melanoma, the high-MIF expression genotype (-173C/C) occurred at higher frequencies compared with healthy controls. These findings highlight that the addition of anti-MIF to anti–PD-1 reduces tumor growth, enhances antitumor responses, prolongs survival, and augments key intratumor immune cell populations involved in immune activation against tumors. This approach merits further consideration for clinical trial development.

Authors

Thuy T. Tran, Gabriela Athziri Sánchez-Zuno, Lais Osmani, Jasmine Caulfield, Caroline Naomi Valdez, Marta Piecychna, Lin Leng, Michelle E. Armstrong, Seamas C. Donnelly, Carlo B. Bifulco, Terri Clister, Rajan P. Kulkarni, Lin Zhang, Mario Sznol, Lucia Jilaveanu, Harriet M. Kluger, Insoo Kang, Richard Bucala

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Figure 2

Reduced MIF expression limits tumor growth and enhances anti–PD-1 efficacy.

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Reduced MIF expression limits tumor growth and enhances anti–PD-1 effica...
(A) MIF protein levels were higher in MC38 than YUMMER1.7 cells by Western blot (MIF:Actin ratio) and by ELISA of supernatant and intracellular protein (MIF levels by pg/mL when 20,000 pg of total protein was added) (unpaired t test). (B and C) YUMMER1.7 tumors grew slower in MIF-knockout (KO) mice compared with WT controls, confirmed by growth curves (1-way ANOVA) and AUC analysis (unpaired t test) at day 14. (D and E) Tumors grew slower in low-MIF CATT5 mice versus high-MIF CATT7 mice, with significantly reduced tumor burden by AUC at day 15 (unpaired t test, P < 0.001). (F and G) Anti–PD-1 treatment further reduced YUMMER1.7 tumor growth in MIF-KO mice (unpaired t test). (H and I) Similar anti–PD-1 effects were seen in CATT5 mice (unpaired t test). Bars indicate SEM; circles show individual data points. Statistical significance is denoted as *P < 0.05, **P < 0.01, ***P < 0.001.