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.
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>.
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.
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.
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.
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.
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.
Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread.
Finally, blocking TGFβ restores the production of IFNα by activated MHCII<sup>+</sup> tumor-associated macrophages, and enables tumor regression induced by STING activation.
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.
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).
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 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.
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.
Dinaciclib induced a type I IFN gene signature within the tumor, leading us to hypothesize that dinaciclib potentiates the effects of anti-PD1 by eliciting ICD.
Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
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.
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.
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.
Moreover, B cells were co-cultured with cASCs, nASCs or mesenchymal stromal cells of the tumor tissue (TSCs) and B cell cytokine production was assessed using flow cytometery. cASCs or TSCs were co-cultured with either intact or B cell depleted lymphocytes and frequencies of CD25<sup>+</sup> FoxP3<sup>+</sup> Tregs, IL-10<sup>+</sup> or IFN-γ<sup>+</sup> CD4<sup>+</sup> T cells were assessed.