Macro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma.

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.

Pan-cancer network disorders revealed by overall and local signaling entropy.

Tumor development is a process involving loss of the differentiation phenotype and acquisition of stem-like characteristics, which is driven by intracellular rewiring of signaling network. The measurement of network reprogramming and disorder would be challenging due to the complexity and heterogeneity of tumors. Here, we proposed signaling entropy (SR) to assess the degree of tumor network disorder. We calculated SR for 33 tumor types in The Cancer Genome Atlas database based on transcriptomic and proteomic data. The SR of tumors was significantly higher than that of normal samples and was highly correlated with cell stemness, cancer type, tumor grade, and metastasis. We further demonstrated the sensitivity and accuracy of using local SR in prognosis prediction and drug response evaluation. Overall, SR could reveal cancer network disorders related to tumor malignant potency, clinical prognosis, and drug response.

Integrated Omics of Metastatic Colorectal Cancer.

We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application.

Breast conserving surgery (BCS) with adjuvant radiation therapy showed improved prognosis compared with mastectomy for early staged triple negative breast cancer patients Running title: BCS had better prognosis than mastectomy for early TNBC patients.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with stronger invasive capacity. For the operation strategies of early staged (stage I and stage II) TNBC patients, BCS plus radiotherapy (BCS+RT), mastectomy only (MRM only) or MRM plus radiotherapy (MRM+RT) is feasible, but no clear conclusion has been made on the choice of these treatments. Methods: The early staged TNBC patients (stage I and stage II) from the Surveillance, Epidemiology and End Results (SEER) program database between 1973 and 2014 were included in the study. Survival curves, univariate and multivariate cox proportional hazards models and propensity score weighting were applied to evaluate the prognostic impact among BCS+RT, MRM only and MRM+RT for patients. Results: Both overall and cancer-specific survival analysis showed that BCS+RT had better prognostic effect than MRM and MRM+RT in the cohort of early-staged triple-negative breast cancer patients (overall survival, P < 0.001; cancer-specific survival, P < 0.001). By taking all the risk factors into a multivariate cox proportional model, MRM and MRM+RT remained to have detrimental effect on the prognosis compared with BCS+RT as shown by either overall (HR = 1.742, CI = 1.387-2.188, P < 0.001; HR = 1.449, CI = 1.038-2.204, P = 0.029) or cancer-specific survival (HR = 1.876, CI = 1.415-2.489, P < 0.001; HR = 1.701, CI = 1.168-2.478, P = 0.006). After we performed propensity score weighting and integrated the weights for each covariate in the multivariate cox proportional model. BCS+RT remained to be prognostic beneficial compared to the other treatment options (P < 0.001). Conclusion: BCS+RT demonstrated better prognosis than MRM only and MRM+RT treatments for early-staged TNBC patients.