Tumor cell phagocytosis (cannibalism) in lung cancer: possible biomarker for tumor immune escape and prognosis.

BACKGROUND: Tumor cell phagocytosis (cannibalism) is rarely seen in lung carcinomas. Little is known about its underlying cellular pathogenesis and associated significance as tumor immune escape mechanism. METHODOLOGY: The cases of lung cancer diagnosed at department of Pathology, VPCI over 13-year period, 2007-2020 (n = 350) were retrospectively reviewed. The cases displaying cannibalism were correlated with their tumor morphology, coexisting inflammation, patient age at presentation, sex, stage/grade, and smoking status. RESULTS: Cannibalism was identified in 10/350 (2.86%) cases of lung cancer. 9/10 (90%) were males and 1/10 (10%) was female. These patients ranged from 48-71 years of age and presented with history of chest pain, anorexia and weight loss. History of smoking was seen in 9/10 (90%) cases while 10% were non-smokers. Mass lesions were seen on CT scan and CT-guided fine needle aspiration cytology (FNAC) was performed. Cytopathology revealed squamous cell carcinoma (5/10, 50%), adenocarcinoma-3/10 (30%), adenosquamous carcinoma (1/10, 10%), and non small cell lung carcinoma (1/10, 10%). No association with small cell carcinoma was seen in our study. Background inflammation and infiltration of acute on chronic inflammatory infiltrate were seen in 6/10 or 60% cases. CONCLUSION: Lung cancers rarely show cannibalism, a tumor immune escape mechanism, even in advanced stage. This phenomenon correlates with squamous cell and adenocarcinoma morphology, tumor associated inflammatory infiltrate, and smoking status. It may be considered as a possible biomarker for tumor immune escape and poor prognosis.

Subtyping of advanced lung cancer based on PD-L1 expression, tumor histopathology and mutation burden (EGFR and KRAS): a study from North India.

Immune checkpoint inhibitor (PD-L1) therapy of advanced non-small-cell lung cancer (NSCLC) has variable outcomes. Tumor subtypes based on PD-L1 expression, histopathology, mutation burden is required for patient stratification and formulation of treatment guidelines. Lung cancers (n=57) diagnosed at Pathology department, VPCI (2018-2021) were retrospectively analyzed. PD-L1(SP263) expressed by tumor cells [low (<1%), medium (1-49%), high (≥50%)] was correlated with histopathology, microenvironment, EGFR, KRAS expression. Patients were categorized into high and low risk based on their: i) gender: males (n=47, 30-89 years), females (n=10, 45-80 years); ii) smoking history: males 26/47 (45.61%), females 1/10 (10%); iii) tumor subtyping: squamous cell carcinoma 15/57 (26.32%), adenocarcinoma 6/57 (17.54%), NSCLC-undifferentiated 24/57 (42.10%), adenosquamous carcinoma 5/57 (8.77 %), carcinosarcoma 4/57 (7.02%), small cell carcinoma 1/57 (1.75%); iv) inflammatory tumor microenvironment/TILs 44/57 (77.1%); iv) PD-L1 positivity-31/57 (54.3%); v) concomitant EGFR/KRAS positivity. PD-L1positive cases showed squamous/undifferentiated histopathology, concomitant EGFR+ (9/20, 45%) and KRAS+ (8/15, 53.3%), smoking+ (21/31,67.74%).PD-L1 negative cases (26/57, 45.6%), were EGFR+ (2/14, 14.28%) and KRAS+ (6/19, 31.5%). The high-risk lung cancer subtypes show squamous/undifferentiated histopathology, inflammatory microenvironment, male preponderance, smoking history, higher concomitant PD-L1, KRAS and EGFR positivity. Lung cancer subtyping can predict clinical response/resistance of patients prior to initiation of PD-L1 inhibitor therapies and can be used to guide therapy.

MicroRNA-based recombinant AAV vector assembly improves efficiency of suicide gene transfer in a murine model of lymphoma.

Recent success in clinical trials with recombinant Adeno-associated virus (AAV)-based gene therapy has redirected efforts in optimizing AAV assembly and production, to improve its potency. We reasoned that inclusion of a small RNA during vector assembly, which specifically alters the phosphorylation status of the packaging cells may be beneficial. We thus employed microRNAs (miR-431, miR-636) identified by their ability to bind AAV genome and also dysregulate Mitogen-activated protein kinase (MAPK) signaling during vector production, by a global transcriptome study in producer cells. A modified vector assembly protocol incorporating a plasmid encoding these microRNAs was developed. AAV2 vectors packaged in the presence of microRNA demonstrated an improved gene transfer potency by 3.7-fold, in vitro. Furthermore, AAV6 serotype vectors encoding an inducible caspase 9 suicide gene, packaged in the presence of miR-636, showed a significant tumor regression (~2.2-fold, P < .01) in a syngeneic murine model of T-cell lymphoma. Taken together, we have demonstrated a simple but effective microRNA-based approach to improve the assembly and potency of suicide gene therapy with AAV vectors.