These results suggest active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T-cells, likely as a result of suppression of IFN response pathways.
Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread.
Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour.
Functionally, induction of ARG1 limited the therapeutic effect of IFN, as inhibition of arginase activity could strongly synergize with poly(I:C) to enhance CD8<sup>+</sup> T cell responses to thwart tumor growth in mice.
Importantly, these Tim-3+ NK cells were functionally diverse, as evidenced by the fact that their ability to produce IFN-γ in response to an NK cell responsive tumor was strictly dependent upon the stimuli employed for Tim-3 induction.
Finally, blocking TGFβ restores the production of IFNα by activated MHCII<sup>+</sup> tumor-associated macrophages, and enables tumor regression induced by STING activation.
FACS was used to determine the frequencies of Tregs, MDSCs, CD4<sup>+</sup> IFN-γ<sup>+</sup> T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR.
Evaluating IFN-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an IFN pathway activator with ICB may be required.<i>This article is highlighted in the In This Issue feature, p. 1143</i>.
IFN fusions selectively induced IP-10 secretion from antigen positive tumor cells, which was critical in recruiting the effector T cells to the tumor microenvironment.
Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN.
Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb).
The PD-1/PD-L1 checkpoint is a central mediator of immunosuppression in the tumor immune microenvironment (TME) and is primarily associated with IFN-g signaling.
Here, we use human tumor explant cultures and cell culture models to show that the (ds) RNA Sendai Virus (SeV), poly-I:C, and rintatolimod (poly-I:C<sub>12</sub>U) all activate the TLR3 pathway involving TRAF3 and IRF3, and induce IFNα, ISG-60, and CXCL10 to promote CTL chemotaxis to <i>ex vivo</i>-treated tumors.
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.
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 treatment of tumor exosomes drastically decreased CD4<sup>+</sup>IFN-γ<sup>+</sup> Th1 differentiation but increased the rates of regulatory T (Treg) cells.
Significant lower ratio of CD3<sup>+</sup>CD4<sup>+</sup> T cells and higher ratio of CD8<sup>+</sup>IFN-γ<sup>+</sup> T cells were found in peripheral blood and tumor tissues in miR-570 mimics than NC.
Elevated IFN-γ within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-γR/STAT1 signaling axis.
This resulted in markedly fewer TNFR2<sup>+</sup> T<sub>reg</sub> cells and more interferon-γ-positive (IFN-γ<sup>+</sup>) CD8<sup>+</sup> cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort.