Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma

• Published in: Nature medicine Vol. 26; no. 1; pp. 39 - 46
• Main Authors: Goswami, Sangeeta, Walle, Thomas, Cornish, Andrew E., Basu, Sreyashi, Anandhan, Swetha, Fernandez, Irina, Vence, Luis, Blando, Jorge, Zhao, Hao, Yadav, Shalini Singh, Ott, Martina, Kong, Ling Y., Heimberger, Amy B., de Groot, John, Sepesi, Boris, Overman, Michael, Kopetz, Scott, Allison, James P., Pe’er, Dana, Sharma, Padmanee
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 5'-Nucleotidase - metabolism; 631/250/251; 631/67/580; Algorithms; Animal models; Animals; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - genetics; Brain Neoplasms - immunology; Brain Neoplasms - therapy; Cancer; Cancer Research; CD73 antigen; Cell Line, Tumor; Clinical trials; Colorectal cancer; Colorectal carcinoma; Combinatorial analysis; CTLA-4 protein; Cytometry; Disease Models, Animal; Drug therapy; Gene Expression Regulation, Neoplastic; Gene sequencing; Glioblastoma; Glioblastoma - diagnostic imaging; Glioblastoma - genetics; Glioblastoma - immunology; Glioblastoma - therapy; Glioblastoma multiforme; GPI-Linked Proteins - metabolism; Health aspects; Humans; Immune checkpoint; Immune response; Immunomodulation; Immunomodulators; Immunotherapy; Infectious Diseases; Letter; Lymphocytes, Tumor-Infiltrating - immunology; Macrophages; Macrophages - metabolism; Magnetic Resonance Imaging; Metabolic Diseases; Methods; Mice, Inbred C57BL; Molecular Medicine; Molecular Targeted Therapy; Myeloid Cells - metabolism; Neurosciences; Nucleotidases; Patients; PD-1 protein; PD-L1 protein; Physiological aspects; Prostate cancer; Receptor antibodies; Ribonucleic acid; RNA; Solid tumors; Therapy; Translation; Tumors; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-019-0694-x

Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types 1 , 2 . Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73 hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73 −/− mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies. Analysis of a mass cytometry dataset for different human solid tumors coupled with murine reverse translational experiments suggests that targeting CD73 could enhance the efficacy of checkpoint inhibitor therapy in glioblastoma.