Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified lecithin cholesterol acyltransferase (LCAT) as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth–promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and to dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC. Significance: Estrogen mediates the sex differences in hepatocellular carcinoma development by reducing cholesterol biosynthesis through activation of an LCAT/HDL-C axis, providing strategies for improving liver cancer prevention, prognosis, and treatment.

Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.

We conducted a retrospective study to evaluate the efficacy of immune checkpoint inhibitor (ICI) rechallenge in patients with advanced non-small cell lung cancer (NSCLC). The study included 111 patients who had previously received ICI therapy and experienced disease progression. The primary endpoints assessed were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Our findings revealed that the ICI rechallenge showed promising results in improving patient outcomes. OS (r) is the time from rechallenging with immune checkpoint inhibitors to the last follow-up or death from any cause. The median OS (r) was 14.3 months (95% CI 11.3–17.3 months), with a median PFS (r) of 5.9 months (95% CI 4.1–7.7 months). The ORR was 17.1%; the DCR was 82.3%. Subgroup analysis demonstrated that patients without brain or liver metastases had a longer OS (r) compared to those with metastases (21.6 vs. 13.8 months, χ² = 3.873, P = 0.046; 20.8 vs. 9.1 months, χ² = 10.733, P = 0.001, respectively). Moreover, patients without driver gene mutations exhibited significantly longer OS than those with mutations or wild-type patients (22.9 vs. 16.1 vs. 7.5 months, χ² = 10.710, P = 0.005). Notably, patients who switched to a different ICI during the rechallenge had shorter OS than those who did not change medications (10.4 vs. 21.1 months, χ² = 9.014, P = 0.003). The incidence of immune-related adverse events did not significantly differ between the two treatment phases. These findings suggest that ICI rechallenge may be a viable therapeutic strategy for select NSCLC patients. Further prospective studies are needed to validate these results and guide treatment decisions for advanced NSCLC.

Objective: The objective of this systematic review and meta-analysis was to determine the prognostic value of memory CD8(+) T cells in cancer patients with immunotherapy. Methods: EMBASE, MEDLINE (PubMed), and Web of Science databases were searched to identify suitabile articles published before March 2021. Risk of bias on the study level was assessed using the Cochrane Bias Risk Assessment Tool. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled progression-free survival (PFS) and overall survival (OS) were calculated using RevMan 5.4 to evaluate the prognostic impact of memory CD8(+) T cells. Results: In total, nine studies were included in the final analysis. High levels of memory CD8(+) T cells were significantly closely correlated with better progression-free survival (PFS) and overall survival (OS) of cancer patients with immunotherapy (PFS, HR 0.64, 95% CI 0.53–0.78; OS, HR 0.37, 95% CI 0.21–0.65). Memory CD8(+) T cells still have significant prognostic value in cancer patients given immunotherapy alone after excluding of other interfering factors such as chemotherapy, radiotherapy, and targeted therapy (PFS, HR 0.65, 95% CI 0.48–0.89; OS, HR 0.23, 95% CI 0.13–0.42). However, high memory CD8(+) T cells levels did not correspond to a longer PFS or OS in cancer patients with non-immunotherapy (PFS, HR 1.05, 95% CI 0.63–1.73; OS, HR 1.29, 95% CI 0.48–3.48). Thus, memory CD8(+) T cells might be a promising predictor in cancer patients with immunotherapy. Conclusions: The host’s overall immune status, and not only the tumor itself, should be considered to predict the efficacy of immunotherapy in cancer patients. This study is the first to show the significant prognostic value of memory CD8(+) T cells in immunotherapy of cancer patients through systematic review and meta-analysis. Thus, the detection of memory CD8(+) T cells has a considerable value in clinical practice in cancer patients with immunotherapy. Memory CD8(+) T cells may be promising immunotherapy targets.

Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Background: Circulating tumor DNA (ctDNA) levels and blood tumor mutation burden (bTMB) have a significant impact on the prognosis of tumor patients. However, their prognostic role in immune checkpoint inhibitors (ICIs) in cancer patients is still unclear.Methods: We used the Review Manager software (version 5.3) to perform a meta-analysis based on the published literature to explore the prognostic value of ctDNA and bTMB in patients receiving immunotherapy. We extracted the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for each included study and their respective 95% confidence intervals (CIs) and p-values for analysis.Results: Thirteen studies were included in the meta-analysis. Higher ctDNA levels were significantly associated with shorter OS (HR = 3.35, 95%CI = 2.49–4.51, p < 0.00001) and PFS (HR = 3.28, 95%CI = 2.47–4.35, p < 0.00001). The results of ctDNA subgroup analysis showed that high posttreatment ctDNA levels significantly correlated with shorter OS in cancer patients receiving ICIs (HR = 5.09, 95%CI = 1.43–18.07, p = 0.01). Moreover, patients with ctDNA clearance had better OS (HR = 4.94, 95%CI = 2.96–8.26, p < 0.00001). Patients with high posttreatment ctDNA levels had shorter PFS (HR = 3.00, 95%CI = 2.02–4.46, p < 0.00001) and those with ctDNA clearance had longer PFS (HR = 4.61, 95%CI = 2.78–7.65, p < 0.00001). However, there was no statistically significant difference in the OS benefits between a high and a low bTMB after ICI therapy (HR = 0.68, 95%CI = 0.33–1.37, p = 0.28).Conclusions: The host immune system and tumor burden together determine whether cancer patients can benefit from ICI therapy. Our systematic review and meta-analysis revealed for the first time that the levels of pretreatment and posttreatment ctDNA and the clearance of ctDNA can independently be used as prognostic factors for antitumor immunotherapy, while bTMB cannot. In conclusion, ctDNA levels have great potential as an assistant tool for radiological assessments to make clinical therapeutic decisions. The prognostic utility of bTMB still requires further exploration.