Tim-3 displays critical roles in microenvironment-induced activation and protumoral effects of TAMs in HCC. Interference of Tim-3 might be great potential in HCC therapy.

Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S 2 < 0.70 vs. S 2 ≥ 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T 1/2 < 22 days versus T 1/2 ≥ 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S 2 < 0.70 versus S 2 ≥ 0.70 (P = 0.025), and 87% vs. 52% with T 1/2 < 22 days versus T 1/2 ≥ 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy. Cancer Res; 70(2); 463-70. ©2010 AACR.

Purpose-To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival.Materials and Methods-Three MRI examinations were obtained in 101 patients before and during therapy (at 2-2.5 and 4-5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional (3D) tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorlyperfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3D-volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t-test, Kaplan-Meier analysis and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 1.2-12.3 years).Results-Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2-2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of ≥30 cm 3 in the MRI obtained at 2-2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, p=0.006) and diseasefree-survival rate (47% vs. 79%, p=0.001), respectively.Conclusions-Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2-2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation and the bulk of residual presumably therapy-resistant tumor, requires future study.

T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), mediating immune exhaustion in tumor microenvironment, has become a promising target for tumor therapy. However, the exact mechanisms for tumor cell-intrinsic Tim-3 in tumor development and its potential contribution in Tim-3-targeted therapy strategy have not been elucidated yet. In this study, we showed that human liver cancer tissues contained high ratio of Tim-3-expressing hepatocytes, and cytokines rich in tumor microenvironment and HBV involved in Tim-3 upregulation in malignant hepatocytes. We demonstrated that hepatocyte-specific Tim-3 overexpression enhances tumor cell growth, whereas Tim-3 inhibition on malignant hepatocytes by anti-Tim-3 antibodies or RNAi suppresses tumor growth both in vitro and in Tim-3 knockout mice. Mechanistically, the hepatocyte-Tim-3 receptor activates NF-κB phosphorylation, which in turn stimulates IL-6 secretion and STAT3 phosphorylation. Our results identify tumor cell-intrinsic functions of Tim-3 in tumorigenesis and suggest that blocking Tim-3 in tumor cells might contribute to the clinical efficacy of anti-Tim-3 antibody treatment in the future tumor therapy.

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