Abstract
Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize the tumor microenvironment for the frequency of GITR expression in T-cell subsets from seven different human solid tumors.Experimental Design: For mouse experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single-cell level using flow cytometry (FC). A total of 213 samples were evaluated for GITR expression by IHC, 63 by FC, and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that NSCLC, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4+ Foxp3+ T regulatory cells. IHC and FC data showed similar trends with a good correlation between both techniques. Human tumor data suggest that NSCLC, renal cell carcinoma, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.
Highlights
Cancer therapies targeting immune checkpoints that are members of the CD28/B7 superfamily (e.g., CTLA-4, PD-1, and PD-L1) have demonstrated a survival benefit in several malignancies, including melanoma [1,2,3,4], renal cell carcinoma [5], non–small cell lung cancer [6, 7], urothelial carcinoma [8], and Hodgkin lymphoma [9]
The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with glucocorticoid-induced TNFR-related protein (GITR) antibody
Analysis of clinical tumor samples showed that non–small cell lung cancer (NSCLC), renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4þ Foxp3þ T regulatory cells
Summary
Cancer therapies targeting immune checkpoints that are members of the CD28/B7 superfamily (e.g., CTLA-4, PD-1, and PD-L1) have demonstrated a survival benefit in several malignancies, including melanoma [1,2,3,4], renal cell carcinoma [5], non–small cell lung cancer [6, 7], urothelial carcinoma [8], and Hodgkin lymphoma [9]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). L. Vence and S.L. Bucktrout contributed to this article
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