The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma
Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia
Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia
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Research Article Immunology Oncology

The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma

Abstract

Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.

Authors

Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia

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Figure 4

The MIF SNP rs755622 correlates with reduced macrophages and increased T cell infiltration by immunofluorescence.

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The MIF SNP rs755622 correlates with reduced macrophages and increased T...
(A) A multiplex panel of myeloid antibodies was developed and included HLA-DR, CD68, CD74, CD11b, P2Ry12, and CD4, with the average expression shown for each cell type identified. (B) The percent of macrophages, MDSCs, microglia, monocytes, and CD4+ T cells and the ratio of MDSCs/CD8+ T cells were calculated as the percent of each cell type per sample out of the total cells identified, and P values were calculated using 2-tailed t test (n = 10 G/G and n = 12 C/G). (C and D) Correlation analyses were performed for immune cell infiltrates from each patient with the major allele genotype (n = 10 G/G) (C) and the minor allele genotype (n = 12) (D). Color scale and circle size are representative of the Pearson correlation coefficient. (E) NanoString spatial profiling comparing regions of n = 8 recurrent glioma samples where areas confirmed to have abnormal nuclear cellularity suggesting cancer were targeted. Comparing differential expression of these treatment response versus progressive regions highlighted increased LTF in treatment-reactive regions. (F) Of note, cases that ultimately presented clinically as treatment reactive had increased enrichment for LTF (***P < 0.001, n = 8).