Lipid-associated macrophages for osimertinib resistance and leptomeningeal metastases in NSCLC.

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1_M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1_M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs.

Expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed small cell lung cancer.

Background: The transformation of epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) into small cell lung cancer (SCLC) accounts for 3-14% of the resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). At present, there is no relevant research to explore the dynamic expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC/neuroendocrine carcinoma (NEC). Methods: Genetic analysis and protein level analysis by next-generation sequencing (NGS), Whole-exome sequencing (WES) and immunohistochemistry were performed to explore expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC. The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment. According to the subsequent treatment regimens after SCLC/NEC transformation, 35 patients were divided into chemo (n=21) and combo (n=14) groups. Results: EGFR L858R and EGFR E746-750 del protein expression by immunohistochemistry was 80.0% (4/5) and 100% (6/6), respectively (P=0.455) in initially-transformed tissues. Meanwhile, EGFR-mutant proteins were expressed in 85.7% (6/7) of dynamic rebiopsy tissues or effusion samples after the first transformation. Then, by the pathway enrichment analysis of tissue and plasma NGS, the EGFR-related pathways were still activated after SCLC/NEC transformation. Moreover, WES analysis revealed that transformed SCLC shared a common clonal origin from the baseline LUAD. The drug sensitivity of three PDOs demonstrated potent anti-cancer activity of EGFR-TKIs plus chemo, compared with chemo or TKI alone. There were significant differences in objective response rate (ORR) between the combo and chemo groups [42.9 % vs. 4.8%, P=0.010, 95% confidence interval (CI): 1.5-145.2]. Furthermore, the median post-transformation progression-free survival (pPFS) was significantly prolonged in the combo group, with 5.4 (95% CI: 3.4-7.4) versus 3.5 (95% CI: 2.7-4.3, P=0.012) months. Conclusions: EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR-mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen.

Pathological characteristics and tumour immune microenvironment of lung malignancies with RET rearrangement.

BACKGROUND: For patients with lung malignancies with RET rearrangement, the efficacy of immune checkpoint inhibitors is limited. The characteristics of the tumour immune microenvironment (TIME) and molecular pathological features of these patients have not been well elucidated. We aimed to investigate their clinical outcomes and explore characteristics of TIME, using multiplex immunohistochemistry technology (mIHC). PATIENTS AND METHODS: The pathology and TIME characteristics of 29 patients with lung malignancies with RET rearrangement were retrospectively analysed, and their relationships with clinical efficacy and prognosis were investigated. Gene detection relied on high-throughput sequencing, and TIME detection was based on mIHC. RESULTS: Of 29 patients, 25(86%) had adenocarcinoma, and the acinar type accounted for the greatest percentage of patients, followed by the solid type, regardless of whether the disease was early or locally advanced and metastatic. In addition, we report a novel KIF5B-RET(k24:R8) rearrangement in pulmonary sarcoma. The density of CD8+ T cells in tumour stroma in early-stage patients was significantly higher than that in locally advanced and metastatic patients (P = 0.014). The proportion of M2 macrophages in tumour stroma was significantly higher than that in tumour parenchyma (P = 0.046). Although the difference was not statistically significant (P = 0.098), patients positive for M2 macrophage infiltration into the tumour parenchyma (≥5%) may have a better prognosis. Seven patients received immunotherapy and disease control rate was 85.7%. CONCLUSIONS: A novel KIF5B-RET rearrangement variant in pulmonary sarcoma shows similar TIME characteristics to lung cancer. amongst patients with lung malignancies with RET rearrangement, patients with M2 macrophage infiltration into the tumour parenchyma may have a better prognosis, but further studies with larger cohorts are needed.

[PI3K p85alpha expression and its role in the progression of colorectal cancer].

OBJECTIVE: To investigate the expression of PI3K p85alpha in normal colorectal tissue, colorectal adenoma and primary colorectal carcinoma and explore its significance in the progression of colorectal cancer. METHODS: The expression of PI3K p85alpha was detected in 116 normal colorectal tissue, colorectal adenoma and primary colorectal carcinoma specimens using immunohistochemical staining, and the relationship between the expression of PI3K p85alpha protein and the clinicopathological factors was analyzed. RESULTS: The positivity rates of the expression of PI3K p85alpha protein increased gradually in the progression of colorectal cancer and showed significant differences between the tissues (P<0.05). A significant difference was also noted in the positivity rates of the PI3K p85alpha expression in colorectal carcinoma tissues at different Dukes' stages (P<0.05). No obvious correlation was found between PI3K p85alpha expression and the degree of the tumor differentiation. CONCLUSIONS: Abnormal PI3K p85alpha expression occurs in the progression of colorectal cancer in close relation to the clinical stage, and the PI3K/AKT pathway plays an important role in the progression of colorectal cancer.