Targeting CD73 May Improve Immunotherapy Efficacy in Glioblastoma

Immune-checkpoint blockade's (ICB) efficacy in some cancer types vastly exceeds its efficacy in other cancer types. Although the reasons for these disparities are not fully understood, some recent studies have pointed to differences in the tumor-infiltrating lymphocyte (TIL) populations associated with different cancer types. Goswami, Walle, Cornish, Basu, and colleagues compared immune infiltrates in tumors from patients with non–small cell lung cancer, renal cell carcinoma, colorectal cancer without microsatellite instability, prostate cancer, and glioblastoma multiforme. This analysis revealed differences in the phenotypes of TILs across these cancer types; of note, CD73^hi macrophages were overrepresented in glioblastomas, which are notoriously resistant to ICB. CD73^hi cells exhibited high expression of MARCO, TGFB, and multiple SIGLEC genes. In data from The Cancer Genome Atlas, this CD73^hi gene signature was associated with poorer overall survival in patients with glioblastoma. Additionally, analysis of glioblastoma samples from patients treated with anti–PD-1 therapy showed that the treatment did not cause a marked shift in the tumor microenvironment, which remained enriched with CD73^hi cells that may have inhibited the infiltration of T cells and contributed to the lack of clinical response to ICB. In a mouse model of glioblastoma, Nt5e (encoding CD73) knockout increased the efficacy of combination therapy with anti–PD-1 and anti-CTLA4. Mechanistically, this enhanced efficacy may have been related to an observed increase in T-cell infiltration and macrophage polarization in Nt5e-knockout mice. In summary, this study provides multiple lines of evidence that CD73 expression may be a key mediator of response to immune-checkpoint blockade. Preclinical and early clinical studies have demonstrated promising results for treatment with anti-CD73, and this study suggests that the addition of anti-CD73 may be a useful strategy to improve outcomes in patients with glioblastoma treated with other immunotherapies.

Goswami S, Walle T, Cornish AE, Basu S, Anandhan S, Fernandez I, Vence L, et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat Med 2020;26:39–46.

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