Precursor exhausted CD8+T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness.

Exhausted CD8+T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8+T cells, termed Tpex cells, which are characterized as TCF-1+PD-1+CD8+T cells. Elevated Tpex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating Tpex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of Tpex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between Tpex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for Tpex cell detection using mIHC technology but also confirmed that assessing Tpex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of Tpex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.

The role of AIM2 in human hepatocellular carcinoma and its clinical significance.

BACKGROUND: AIM2 (absent in melanoma 2) was first discovered as the gene which was not expressed in melanoma cells. It is established that the AIM2 inflammasome function as the double-stranded DNA (dsDNA) sensor, and it plays a crucial role in infectious disorders and cancer. Little is known about the AIM2 expression pattern and its clinical significance in human hepatocellular carcinoma (HCC), understating how AIM2 altered the HCC cells is of high clinical interest. METHODS: Immunohistochemistry was performed to investigate the AIM2 expression in HCC tissues. Then we constructed the ectopic AIM2-expressed HCC cell line by lentiviral transduction. Biological functional assays were used to analyze the clinical significance of AIM2. RESULTS: AIM2 expression was significantly decreased in human HCC tissues compared with adjacent normal tissues, and the overall survival of HCC patients with higher AIM2 expression was significantly better. Ectopic expression of AIM2 in HCC cells significantly inhibited migration and promoted apoptosis. Furthermore, our study revealed that the notch signaling pathway could be involved in the regulation of AIM2 in the cellular network in HCC cells. AIM2 delayed the tumor progression and correlated with immune cell infiltration. CONCLUSION: In this study, we suggested AIM2 played an inhibitory role in regulating the growth and metastasis of HCC, which supported the notion that AIM2 could serve as a potential therapeutic target for HCC.

The CXCL10/CXCR3 Pathway Contributes to the Synergy of Thermal Ablation and PD-1 Blockade Therapy against Tumors.

As a practical local therapeutic approach to destroy tumor tissue, thermal ablation can activate tumor-specific T cells via enhancing tumor antigen presentation to the immune system. In the present study, we investigated changes in infiltrating immune cells in tumor tissues from the non-radiofrequency ablation (RFA) side by analyzing single-cell RNA sequencing (scRNA-seq) data of tumor-bearing mice compared with control tumors. We showed that ablation treatment could increase the proportion of CD8+T cells and the interaction between macrophages and T cells was altered. Another thermal ablation treatment, microwave ablation (MWA), increased the enrichment of signaling pathways for chemotaxis and chemokine response and was associated with the chemokine CXCL10. In addition, the immune checkpoint PD-1 was especially up-regulated in the infiltrating T cells of tumors on the non-ablation side after thermal ablation treatment. Combination therapy of ablation and PD-1 blockade had a synergistic anti-tumor effect. Furthermore, we found that the CXCL10/CXCR3 axis contributed to the therapeutic efficacy of ablation combined with anti-PD-1 therapy, and activation of the CXCL10/CXCR3 signaling pathway might improve the synergistic effect of this combination treatment against solid tumors.

TIGIT Blockade Exerts Synergistic Effects on Microwave Ablation Against Cancer.

Background: Combination immunotherapy based on immune checkpoint inhibitors (ICIs) has shown great success in the treatment of many types of cancers and has become the mainstream in the comprehensive treatment of cancers. Ablation in combination with immunotherapy has achieved tremendous efficacy in some preclinical and clinical studies. To date, our team proved that ablation in combination with ICIs was a promising antitumor therapeutic strategy for the liver metastasis of colorectal cancer (CRC). Moreover, we found that the expression of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was up-regulated after microwave ablation (MWA), indicating that TIGIT was involved in immunosuppression, and the combination of MWA and TIGIT blockade represented a potential clinical treatment strategy. Methods: In the present study, we examined the expression of TIGIT using a preclinical mouse model treated with MWA. Moreover, we evaluated the antitumor functions of MWA alone or in combination with TIGIT blockade by monitoring tumor growth and survival of the mice. Besides, we also detected the numbers of tumor-infiltrating lymphocytes (TILs), and effector molecules of CD8+ T cells using flow cytometry. Finally, we analyzed the single-cell RNA sequencing (scRNA-seq) data from the MWA and MWA plus anti-TIGIT groups. Results: The expression of TIGIT in various immune cells was up-regulated after MWA, and the addition of TIGIT blockade to MWA prolonged survival and delayed tumor growth in the MC38 tumor model. Taken together, our findings showed that TIGIT blockade in combination with MWA significantly promoted the expansion and functions of CD8+ TILs and reshaped myeloid cells in the tumor microenvironment (TME) using flow cytometry and scRNA-seq analysis. Conclusions: TIGIT blockade in combination with MWA was a novel treatment strategy for the liver metastasis of CRC, and this combination therapy could reprogram the TME toward an antitumor environment.

Expression of HHLA2 in hepatocellular carcinoma tissues and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of human endogenous retrovirus subfamily H long terminal repeat associating protein 2 (HHLA2) in hepatocellular carcinoma (HCC) tissues and its correlation with the clinicopathological characteristics and prognosis of patients with HCC. Methods: Based on TCGA database, the correlation between HHLA2 mRNA expression and B7 family genes in human HCC tissues was analyzed. HHLA2 expression in 90 pairs of HCC tissues and their adjacent tissues was detected by tissue microarry and immunohistochemical staining. Wilcoxon rank sum test was used to compare the difference of HHLA2 expression between HCC tissues and its adjacent tissues. The chi-square test was used to analyze the relationship between HHLA2 expression in human HCC tissues and clinicopathological features of the patients. Kaplan-Meier survival analysis was performed to analyze the correlation between HHLA2 expression and patients’ overall survival (OS), and the Cox model was used to evaluate the prognostic value of different indices. Results: The expression level of HHLA2 mRNA in HCC tissues was correlated with B7 family CD274, C10orf54, PDCD1LG2, ICOSLG and CD276. The expression level of HHLA2 in HCC tissues was significantly correlated with tumor size (χ2=4.531, P<0.05). The OS of HCC patients with high HHLA2 expression was significantly shorter than that of the patients with lower HHLA2 expression (HR=1.878, 95%CI: 1.066-3.309, P<0.05). The COX model showed that tumor size (HR=2.493, 95%CI: 1.310-4.742, P<0.01) could be used as an independent risk factor for the prognostic prediction of the patients. Conclusion: HHLA2 is significantly correlated with the prognosis of HCC patients, and can be used as a potential target for HCC immunotherapy.

Decreased IFIT2 Expression In Human Non-Small-Cell Lung Cancer Tissues Is Associated With Cancer Progression And Poor Survival Of The Patients.

BACKGROUND: IFIT2 (interferon-induced proteins with tetratricopeptide repeats 2), also known as ISG54, is an important interferon-stimulated gene family protein, which has been confirmed to play a crucial role in anti-cancer as well as anti-virus process. In the present study, we aimed to investigate the IFIT2 expression in human non-small-cell cancer (NSCLC) tissues and its clinical implications. METHODS: The immunohistochemistry assay was used to identify the clinical significance and prognostic value of IFIT2 expression in NSCLC tissues. The depletion of IFIT2 was achieved using RNAi approach to assess the role of IFIT2 in the regulation of biological behaviors in human lung cancer cell lines. RESULTS: Decreased IFIT2 expression was found in human NSCLC tissues (both in lung adenocarcinoma and lung squamous cell carcinoma) in contrast to the adjacent normal tissues (both P<0.0001, respectively). We did not find any significant correlations between the IFIT2 expression and patient's clinicopathological features. The survival analysis showed that the overall survival (OS) of patients in IFIT2 low expression group was significantly poorer than that in IFIT2 high expression group (in lung adenocarcinoma: P=0.027; and in lung squamous cell carcinoma: P=0.029). The Cox model analysis also indicated that the distant metastasis (P=0.043) could be used as an independent prognostic factor for lung adenocarcinoma patients, and the lymph node metastasis (P=0.045) and IFIT2 low expression (P=0.020) could be used as independent prognostic factors for lung squamous cell carcinoma patients. Moreover, the depletion of IFIT2 in human lung cancer cell lines A549, H1975 and SK-MES-1 significantly increased the cellular abilities, such as viability, migration and invasion. CONCLUSION: Decreased IFIT2 was involved in the initiation and the progression of human NSCLC, and its underlying mechanisms still needs further investigation.

Mechanism of regularatory T cells in tumor immunity and the new strategy of treatment / 中国肿瘤生物治疗杂志

@#调节性T（regulatory T，Treg）细胞是一类控制体内免疫反应性的T细胞亚群，在维持机体的免疫系统稳态和调节免疫 应答方面具有重要作用，并且发现在多种肿瘤类型中以较高比例存在，被认为是产生抗肿瘤免疫应答的主要障碍。Treg细胞在 其功能状态和稳定性方面存在异质性，通过多种机制发挥免疫负调控作用，目前在自身免疫和肿瘤免疫的研究中发现，特异性调 节不同Treg细胞群体可改善免疫疗效。但是，如何更加合理有效的以Treg细胞为靶点抑制肿瘤的进展仍需进一步探索。本文就 Treg细胞在肿瘤免疫中的作用机制及治疗应用新策略展开综述。