Mechanisms to Redirect Tumor Associated Macrophages to Target Retinoblastoma Cells
Retinoblastoma is a pediatric tumor of the retina that is usually curable if detected early in high income countries, but children with chemo-resistant, disseminated or metastatic disease have few effective therapeutic options. This study is on the important issue of how macrophage immune cells interact with retinoblastoma tumors to promote their growth or regression. Using a mouse model of retinoblastoma developed in our lab, we identified immune transcripts and cells in the tumors, identified the same transcripts in human retinoblastoma, and found their expression was highest in weakly proliferating tumors. The work was initially challenged, in part owing to widely held belief that “immune infiltration is not typically observed in human retinoblastoma”. But new studies using primary human tumors clearly demonstrate they are present in all tumors and are very abundant in around half. The field needs our aggressive model of retinoblastoma in which we can modulate macrophages in an immune proficient setting. We hypothesize that tumor associated macrophages (TAMs) suppress immune mediated retinoblastoma tumor cell death. We expect that therapies that either eliminate TAMs completely or engage their anti-tumor properties will promote tumor regression.
Project Goal:
We hypothesize that tumor associated macrophages (TAMs) suppress immune mediated retinoblastoma tumor cell death and that therapies that either eliminate TAMs completely or engage their anti-tumor properties will promote tumor regression. Specific Aim 1 will test if depleting macrophages by blocking colony stimulating factor-1 receptor (CSF1R) survival signaling using either a CSF1R pharmacologic inhibitor or an anti-CSF1R antagonistic monoclonal antibody (mAb) induces retinoblastoma tumor regression in vivo. Specific Aim 2 will exploit the plasticity of TAMs using different strategies to engage their inflammatory and tumoricidal properties and reverse their immune-suppressive functions. First, we will use an agonist mAb against the CD40 molecule, a co-stimulatory member of the TNF-receptor superfamily, which can promote macrophage infiltration into tumors and engage their tumoridical activity. Second, we will activate toll-like receptor 3 (TLR3) with the poly-ICLC agonist. We’re supported by outstanding contributors with expertise targeting TAMs in cancer, leukocyte flow cytometry to determine the identity and timing of the compensatory immune cell infiltration, and pathologists to score the anti-tumor response.
