Cancer Biology & Therapy最新文献

Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.

Lung cancer, one of the most prevalent tumors, remains a clinical challenge with a poor five-year survival rate. Daurisoline, a bis-benzylisoquinoline alkaloid derived from the traditional Chinese herb Menispermum dauricum, is known to suppress tumor growth effectively. However, its precise mechanism of action remains unclear. In this study, we demonstrate that Daurisoline targets glycolysis and reduces the protein level of HK2, thereby inhibiting lung cancer progression. Mechanistic investigations reveal that Daurisoline directly binds to AKT and antagonizes the AKT-GSK3β-c-Myc-HK2 signaling axis. Furthermore, in an animal model, we validate the in vivo anti-tumor effect of Daurisoline without any observable side effects. Overall, our findings suggest that Daurisoline holds potential as an anti-tumor agent through its targeting of glycolysis.

Purpose: Neoadjuvant chemotherapy (NAC) has proven valuable in treating locally advanced colon cancer (LACC) and is included as a treatment option for patients with clinical T4b colon cancer by the National Comprehensive Cancer Network. However, the long-term survival benefit of NAC in LACC remains debated, due to a lack of conclusive clinical trial results identifying the patients who would benefit most from NAC. This study aimed to assess the efficacy of NAC in patients with LACC based on histological subtype.

Patients and methods: This retrospective study analyzed 3,709 patients with LACC who underwent curative resection at Harbin Medical University Cancer Hospital between 2014 and 2018. Patients were grouped into two groups: neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) groups. Propensity score matching (PSM) was used to adjust for confounders, and survival outcomes of the two groups across different histological subtypes were evaluated using Kaplan-Meier (K-M) curves and log-rank tests.

Results: Patients with non-mucinous adenocarcinoma (NMAC) treated with NAC had a significantly improved 5-year OS rate (76.3% vs. 69.2%, p = .039) and DFS rate (67.2% vs. 60.1%, p = .041) compared with patients treated with AC. However, there was no significant difference in OS and DFS between the two treatment groups among patients with mucinous adenocarcinoma (MAC) and signet ring cell carcinoma (SRCC).

Conclusion: In patients with LACC, the prognostic value of NAC varied by histology. NMAC may serve as a predictor of improved long-term survival benefit from NAC in these patients.

Endostar is a human recombinant endostatin which is an attractive anti-angiogenesis protein. Because inefficient antigen presenting MHC class I expression (which can be downregulated by HIF-1) is an important strategy for cancer immune evasion, besides its anti-angiogenesis effect, it remains unclear whether Endostar has an inhibitory effect on HIF-1 expression by upregulating MHC class I expression in cancer cells to facilitate immunotherapies, including PD-1/PD-L1 inhibitors. In this study, A549 and NCI-H1299 lung cancer cells were treated with Endostar (6.25 μg/ml, 12.5 μg/ml, and 25 μg/ml, respectively). HIF-1 expression was detected by Immunocytochemistry and Western blot. Proteins of the MHC class I α-heavy chain and β2 m light chain, STAT3 and pSTAT3 were detected by Western blot. The mRNAs of MHC class I α-heavy chain and β2 m light chain were detected by RT-qPCR. It was shown that decreased expression of HIF-1 and promotion of β2-microglobulin were observed after Endostar treatment. In addition, elevated levels of MHC class I α-heavy chain mRNA and protein, as well as downregulation of STAT3 and pSTAT3, were also observed following Endostar treatment. Endostar inhibited HIF-1 expression in A549 and NCI-H1299 lung cancer cells, upregulated expression of MHC class I α-heavy chain and β2 m light chain, with the upregulation of STAT3 and pSTAT3, suggesting involvement of STAT3 pathway. It is important because only in combination with MHC class I on target cells can tumor antigenic peptides be recognized by CD8+ CTLs which destroy target cells. However, MHC class I is frequently deficient in cancer cells.

Bladder cancer (BC) remains challenging due to its recurrence and metastasis, with METTL3-mediated m⁶ A RNA modification emerging as a key oncogenic driver. This review synthesizes METTL3's roles in BC progression, including tumor initiation, metastasis, stemness, and therapy resistance. We detail its regulation of critical pathways (e.g. HIF1A/IGF2BP3/BIRC5, AFF4/NF-κB/c-MYC) and dual functions in RNA stability and epigenetic crosstalk with DNA methylation. METTL3 promotes chemoresistance (e.g. circ0008399/WTAP/TNFAIP3) and immune evasion (PD-L1 stabilization), while its overexpression correlates with poor prognosis and cisplatin resistance. By integrating METTL3's interactions with m⁶ A readers (YTHDF1/2, IGF2BP3) and erasers (ALKBH5), we propose targeting METTL3 as a strategy to enhance chemotherapy and immunotherapy efficacy. This work underscores METTL3's potential as a diagnostic biomarker and therapeutic target, advancing precision oncology in BC.

Targeted therapy-induced resistance is a significant factor contributing to treatment failure in patients with gastrointestinal stromal tumors (GIST). Despite the identification of the long non-coding RNA (lncRNA) OIP5-AS1 as a critical player in human malignancy development, its role in GIST-related drug resistance remains largely unexplored. This study revealed substantial up-regulation of both OIP5-AS1 and SOX9, alongside significant down-regulation of miR-145, within sunitinib-resistant GIST cells. OIP5-AS1 emerged as a competing endogenous RNA, exerting inhibition on miR-145 while concurrently promoting the expression of SOX9. Exosome-mediated transfer of OIP5-AS1 induced heightened proliferation and invasion of GIST cells, culminating in the induction of chemoresistance to sunitinib through the miR-145/SOX9 axis. The knockdown of OIP5-AS1-expressing exosomes resulted in reduced cell proliferation and invasion in chemo-resistant GIST cells. In summary, these findings collectively suggest that OIP5-AS1 fosters GIST cell proliferation and invasion by suppressing miR-145 and up-regulating SOX9, ultimately contributing to drug resistance and tumor progression in GIST.

Background: Peptide vaccines offer a direct way to initiate an immunogenic response to a defined antigen epitope. However, peptide vaccines are unstable in vivo, subject to rapid enzymatic proteolysis. Replacement of an α-amino acid residue with a homologous β-amino acid residue (native side chain, but backbone extended by a single CH₂ unit) impairs proteolysis at nearby amide bonds. Therefore, antigen analogues containing α-to-β replacements have been examined for functional mimicry of native all-α antigens. Another group previously took this approach in the ovalbumin (OVA) antigen model by evaluating single α-to-β analogues of the murine major histocompatibility complex (MHC) I-restricted peptide SIINFEKL.

Methods: We re-examined this set of α/β SIINFEKL antigens. We tested the susceptibility to proteolysis in mouse serum and their ability to activate OVA-antigen-specific CD8 T cells in vitro. Additionally, we tested the α/β antigens in vivo for their ability to induce an antigen-specific immunogenic response in naïve mice and in OVA-expressing tumor-bearing mice.

Results: The α/β antigens were comparable to the native antigen in their susceptibility to proteolysis in serum. Each α/β antigen was capable of activating antigen-specific CD8 T cells in vitro. However, antigen-specific CD8 T cells induced against α/β antigens in vivo were not cross-reactive to the native antigen. Moreover, immunization with α/β analogues did not elicit anti-tumor effects in tumor-bearing mice.

Conclusions: We conclude that even though α/β analogues of the SIINFEKL antigen can elicit a T cell-based response, this class of backbone-modified peptides is not promising from the perspective of antitumor vaccine development.

This study was conducted to investigate the in vitro differences in killing effects and cellular death pathways in human bronchial epithelial BEAS-2B cells, human lung adenocarcinoma A549 cells, human lung squamous carcinoma H520 cells, and human lung small cell carcinoma H446 cells mediated by hematoporphyrin derivative (HPD) at 630 nm laser wavelength. Our results showed that the viability of the BEAS-2B, A549, H520, and H446 cells gradually decreased with increasing HPD concentration after HPD-PDT. HPD-PDT induced an increase in intracellular ROS production (p < 0.05), with H520 > A549 > H446 > BEAS-2B. HPD-PDT resulted in intracellular chromatin fixation and dense nuclear staining and induced apoptosis, with apoptosis rates of H520 > A549 > H446 > BEAS-2B. The western blotting (WB) results showed that HPD-PDT could lead to reduced BCL-2 protein levels, upregulate BAX protein expression and activate caspase-3 protein, and induce autophagy, as evidenced by the increased expression of the autophagy-related proteins ATG5, Beclin-1 and LC3B in all cells tested. However, apoptosis-inducing proteins and autophagy proteins were statistically different in these four cell types. Our study confirms that HPD-mediated phototoxicity varied in the different cell lines, indicating that lung cancer cells die due to the interactions of different cell death pathways rather than the same well-defined mechanisms.

Trial registration: Trial no. NCT04821778 registered in ClinicalTrials.gov.