Most importantly, PSar-IFN is significantly more potent in inhibiting tumor growth and elicits considerably less anti-IFN antibodies in mouse than PEG-IFN.
Our analysis demonstrates that tumors infiltrated by CD8<sup>+</sup> T cells expressing higher levels of activation marker (PD1<sup>hi</sup>) along with TCR signaling genes and cytolytic T cell markers (IL2<sup>hi</sup>/TNF-α<sup>hi</sup>/IFN-γ<sup>hi</sup>/GZMA-B<sup>hi</sup>) extend survival, whereas survival benefit was absent for tumors infiltrated by anergic and hyperexhausted CD8<sup>+</sup> T cells characterized by high expression of <i>CTLA-4, TIM3, LAG3</i>, and genes linked to PI3K signaling pathway.
The primary endpoint was the association between tumour hMLH1 or/and hMSH2-deficient and VEGF-1 expression; the relation between tumour MMR-status and IFL response rate was the secondary endpoint.
Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events.Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.
Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 or IFN-α.
IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal.
Emodin also sensitized the antiproliferative effect of IFN-α in HeLa cervical carcinoma cells and reduced tumor growth in Huh7 hepatocellular carcinoma-bearing mice.
According to qRT-PCR data, expression levels of the endoplasmic reticulum-nuclei-1 (ERN1), Toll-like receptor 2 (TLR2), and human IFN regulatory factor 5 (IRF5) tumor suppressor genes elevated 2.05-, 2.08-, and 2.3-fold by ZA, respectively, in U87MG cells.
These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination.
The level of IFN- or TNF- in the serum was detected and lymphocyte infiltration in the tumor tissue; the ratios of CD8+ T cells and CD4+ T cells in the spleen of mice were also analyzed.
The IFN- secreted from CD8<sup>+</sup> T cells in the spleen also contributed to the better tumor inhibition profile in BIPI treatment group than in anti-PD-L1 or IL-2 treatment alone.
Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor.
Our results show that IFN-α mRNA electroporation of DCs significantly increases the stimulation of tumor antigen-specific cytotoxic T cell as well as anti-tumor NK cell effector functions in vitro through high levels of IFN-α secretion.
Recent evidence has indicated that spontaneous activation of the Stimulator of Interferon Genes (STING) pathway within tumor-resident dendritic cells leads to type I IFN production and adaptive immune responses against tumors.
Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes and the cross-priming of Ag-specific CD8(+) T cell responses associated with therapeutic benefit.
Notably, nuclear ATF2 and low expression of IFNβ1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-α2a.
The concentration of a Treg-inhibitory cytokine, interleukin (IL)-6, was correlated with the IFN-α expression level in tumors, and intratumoral CD11c(+) cells produced IL-6 in response to IFN-α stimulation.
A complex prognostic interaction was revealed in ESR1+/ERBB2- and ERBB2+ tumors when the association between the IFN metagene and a T-cell metagene was considered.
Using a unique inducible expression system to increase local levels of IFN-α exogenously, we show here that the capacity of radiation therapy to result in tumor control can be enhanced.