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TIM3 expression on tumor cells predicts response to anti-PD-1 therapy for renal cancer.

ABSTRACT: This study aimed to identify novel prognostic biomarker for advanced renal cell carcinoma (RCC) patients treated with anti-PD-1 therapy, using quantitative multi-immunofluorescence (IF) analysis of tumor immunity. Twenty-five consecutive patients who had metastatic or unresectable RCC treated with anti-PD-1 therapy were studied. The patients were divided into a responder group (n = 12) and a non-responder group (n = 13). Quantitative multi-IF staining was performed on biopsy or surgical kidney samples using a panel of antibodies. Sections were scanned using a Mantra microscope, and the images were analyzed with inForm™ software. Responders had significantly higher rate of TIM3-positive tumor (100% versus 53.9%, p < 0.01) than non-responders. Multi-IF analysis showed that TIM3 expression on tumor cells was most strongly related to response to anti-PD-1 therapy, while some of the known immune-related prognostic factors in RCC (CD45RO, FOXP3, VEGF, PD-L1, PD-L2, CD163) had no significant association. Patients with TIM3-positive tumor showed significantly longer overall survival (not reached median time versus 6.0 months, p < 0.01) and progression-free survival (18.9 versus 1.1 months, p < 0.01) than those with TIM3-negative tumor. Immunohistochemistry study using samples obtained after anti-PD-1 therapy showed infiltration of CD163 macrophages and release of HMGB1, a ligand of TIM3, in necrotic tumor area. In conclusion, our study found clinical correlation between TIM3 expression on tumor cells and response to anti-PD-1 therapy. Further studies are warranted to verify whether TIM3 expression on tumor cells before systemic therapy predicts the efficacy of anti-PD-1 therapy for RCC in the clinical setting.

SUBMITTER: Kato R

PROVIDER: S-EPMC7586238 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS:The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS:The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-? level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-? induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-?-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-? level. By combining the relative expression of the listed IFN-?-induced genes, IFN-? score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION:Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-? is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-? score aggregated from the expressions of the listed IFN-?-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

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TIM3 expression on tumor cells predicts response to anti-PD-1 therapy for renal cancer.

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