Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been reported to be involved in the progression, metastasis and recurrence of malignancies. However, the potential role of LPCAT1 in NSCLC remains poorly understood. This study was aimed to identify genes involved in lung adenocarcinoma (LUAD) brain metastasis, and look into the role of LPCAT1 in LUAD progression. We used integrative genomic analysis to identify genes involved in lung adenocarcinomas. LPCAT1 expression was evaluated in tumor tissues from LUAD patients and LUAD cell lines. The role of LPCAT1 was subsequently investigated both in vitro and in vivo. The mechanism underlying the involvement of LPCAT1 in LUAD progression was explored with the activator of PI3K/AKT pathway. RNA sequencing was performed to confirm the involvement of LPCAT1 and associated pathway in LUAD brain metastasis. LPCAT1 was up-regulated in LUAD tissues and cell lines. shRNA-mediated depletion of LPCAT1 not only abrogated cell proliferation, migration and invasion in vitro, but also arrested tumor growth and brain metastases in vivo. Notably, LPCAT1 at least partially influenced LUAD progression through PI3K/AKT signal pathway by targeting MYC transcription. Moreover, expression of LPCAT1 was higher in tissues of LUAD patients with BM than those without BM as revealed by IHC staining, RNA-Sequencing and qPCR analysis. Finally, elevated LPCAT1 expression in patients with lung adenocarcinomas was associated with a poor clinical outcome. This study showed that LPCAT1 works as a regulator of cell metastasis and may serve as a novel therapeutic target for BM in lung adenocarcinoma.

The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4⁺ and CD8⁺ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.

Background: Oncolytic virus (OV)-mediated immunotherapy has been shown limited efficacy. Small molecule inhibitors specific to the KRAS^G12C driver oncoprotein have recently been developed for cancer treatment. The combination of a potent OV with a KRAS^G12C inhibitor could be a potent combination strategy for treating KRAS^G12C cancer. Methods: We explored combination therapies using KRAS^G12C inhibitor and OV in cancer cells in vitro and in two KRAS^G12C cancer models. We employed flow cytometry to evaluate the immune cell profiles, including dendritic cells, macrophages, myeloid-derived suppressor cells, natural killer (NK), subsets of CD4⁺ and CD8⁺ T cells, and exhaustion markers (CTLA-4, PD-1, TIM-3), activation markers (granzyme B, IFN-γ and 4-1BB) as well as enzyme-linked immunospot assay to identify tumor-antigen specific T cells. The importance of CD4⁺, CD8⁺ T and NK cells in the therapeutic effects was evaluated by antibody-mediated depletion in vivo. Results: We confirmed that three inhibitors for KRAS^G12C, AMG510 (sotorasib), MRTX849 (adagrasib) and MRTX1257, all displayed potent cytotoxicity to cancer cells harboring KRAS^G12C, but not to cancer cells without this specific KRAS mutation in vitro. All three inhibitors exhibited potent antitumor activity in KRAS^G12C Lewis lung cancer, but not in MC38 colon cancer with wild-type KRAS. In two KRAS^G12C tumor models, either an IL-36γ-armed OV or orally delivered MRTX1257 inhibited tumor growth, but the combination worked much more efficiently, and efficacy was further improved with PD-1 blockade although with no statistical difference in survival, leading to complete tumor remission in a large fraction of the mice. Mechanistic studies revealed that MRTX1257, and other KRAS^G12C inhibitors as well, are potent inducers of antitumor immunity by themselves, and that it worked with OV to elicit potent innate and adaptive tumor-specific immunity. The combination therapeutic efficacy depended largely on increased tumor-specific CD8⁺ cytotoxic T cells, and to a smaller degree, on CD4⁺ T and NK cells. Conclusions: Small molecule inhibitors of KRAS^G12C are novel inducers of tumor-specific immunity, and a unique triple combination regimen is highly efficacious through elicited potent antitumor immunity for KRAS^G12C cancers.

Background: Immune checkpoint inhibitors, including anti-PD-1 therapies, have prolonged overall survival in patients with a variety of cancers, and immunotherapy is sometimes associated with immune-related adverse events (irAEs); however, hematological toxicity, especially neutropenia, is rare.Case presentation: A 78-year-old man with squamous lung cancer, with brain metastasis, was treated with pembrolizumab and albumin-bound paclitaxel as first-line treatment for one cycle and changed to pembrolizumab plus anlotinib at the second cycle. After two therapy cycles, grade 4 neutropenia developed, which mainly contributed to irAEs. The patient was started on granulocyte colony-stimulating factor (G-CSF) but did not improve; he was then treated with corticosteroids, and neutrophil counts gradually returned to normal levels. However, the patient eventually died because of neurological problems.Conclusion: Grade 4 neutropenia associated with ICI, although rare, is often severe and presents with infectious complications; it needs to be diagnosed early, and clinicians should ensure prompt and proper management to such patients.