HIV Associated Lung Cancer: Unique Clinicopathologic Features and Immune Biomarkers Impacting Lung Cancer Screening and Management.

OBJECTIVES: Lung cancer contributes significantly to morbidity and mortality in people with HIV (PWH). We study the clinicopathologic characteristics and immune microenvironment in HIV associated lung cancer. MATERIAL AND METHODS: Clinicopathological characteristics including immunotherapy outcomes were collected for 174 PWH diagnosed with lung cancer. Immunohistochemical staining for PD-L1, CD4, and CD8 was performed. RESULTS: At diagnosis, patients with HIV associated lung cancer were significantly younger (56.9 vs. 69 years, P < .0001) and more frequently had advanced disease (70% vs. 53%, P = .01). The majority were African American (60% vs. 42%, P < .0001) and were smoking at the time of diagnosis or smoked in the past (98% vs. 86%, P = .0001). Only 10% of HIV associated lung cancer was diagnosed through the screening program. The median CD4+ lymphocyte count was 334 cells/µL, 31% had a CD4 ≤200 cells/µL and 63% of the cohort was virally suppressed. HIV associated non-small-cell lung cancer(NSCLC) was characterized by limited PD-L1 expression compared to the HIV negative cohort, 64% vs. 31% had TPS <1%, and 20% vs. 34% had TPS≥50%, respectively (P = .04). Higher CD8+ TILs were detected in PD-L1-high tumors (P < .0001). 50% of patients achieved disease control in the metastatic setting with the use of immunotherapy, and there were no new safety signals in 19 PWH treated with immunotherapy. CONCLUSION: Lung cancer in PWH demonstrates unique features highlighting the need for a specialized screening program. Despite low PD-L1 expression, immunotherapy is well tolerated with reasonable disease control. Altered immune system in lung cancer pathogenesis in PWH should be further investigated.

Aurora Kinase A Inhibition Potentiates Platinum and Radiation Cytotoxicity in Non-Small-Cell Lung Cancer Cells and Induces Expression of Alternative Immune Checkpoints.

Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA's role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways.

Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, p = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.

Targeted Therapies for Breast Cancer Brain Metastases.

The management of breast cancer, the most common cancer in the female population, has changed dramatically over years with the introduction of newer therapies. An increased incidence of brain metastases in recent years has created a challenge for oncologists because this population continues to have a poorer prognosis compared to metastatic breast cancer without central nervous system involvement. Historically, the exclusion of breast cancer patients with brain metastases from clinical trials has made treatment options even more limited. Nonetheless, more recently, this unmet need has been recognized by basic and clinical researchers and has led to the development of targeted therapies with better blood-brain barrier penetration and intracranial efficacy. Here we review targeted therapies directed at human epidermal growth factor receptor type 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 and 6 (CDK4/6) and poly(ADP-ribose) polymerase (PARP) for breast cancer patients with brain metastases. These therapies aim to be more efficacious and less toxic to represent a paradigm shift in the management of breast cancer brain metastases.

Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma.

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.

Gene co-expression network analysis of dysferlinopathy: Altered cellular processes and functional prediction of TOR1AIP1, a novel muscular dystrophy gene.

Dysferlinopathy, caused by a dysferlin gene mutation, is a clinically heterogeneous autosomal recessive muscle disease characterized by progressive muscle degeneration. The dysferlin protein's functions and dysferlinopathy disease pathogenesis are not fully explored, and there is no specific treatment available that can alter the disease progression. This study uses publicly available dysferlinopathy patient microarray data to construct a gene co-expression network and investigates significant cellular pathways and their key players in dysferlinopathy pathogenesis. Extracellular matrix deposition, inflammation, mitochondrial abnormalities and protein degradation were found to be important in dysferlinopathy. Out of the hub genes, OXR1 and TIMP1 were selected through literature search as candidate genes for possible biomarker and molecular therapeutic target studies. A recently identified muscular dystrophy gene TOR1AIP1 was detected as a hub gene in dysferlinopathy. Co-expression and protein sequence feature analysis were adopted to predict TOR1AIP1's function. Our results suggest that LAP1 protein encoded by TOR1AIP1 may play a role in protein degradation possibly through transcriptional regulation in muscle tissue. These findings extend dysferlinopathy pathogenesis by presenting key genes and also suggest a novel function for a poorly characterized gene.