Animals in which complete tumor regression occurred with combination treatments were resistant to secondary tumor challenge and presented heightened expression levels of splenocyte-produced IFNγ.
Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer.
Cd69-/- mice showed reduced tumor growth and metastasis in a 4T1-luc2 murine breast cancer model, in which increased numbers of tumor-infiltrating lymphocytes, relatively little T-cell exhaustion, and enhanced IFNγ production were observed.
Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer.
The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of AIT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer.
(i) Like normal kidney, virtually all primary human renal cell carcinomas express MHC class I antigens and retain this phenotype even during tumor progression and metastasis; (ii) class II expression on normal and RCC cells appears more limited but occurs frequently in both primary and metastatic lesions; and (iii) in most continuous RCC cell lines expression of MHC class I and II can effectively be stimulated by IFN-gamma.
The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites.
Overall, the results indicated that IFN-γ induces gastric cancer cell proliferation and metastasis partially through the upregulation of integrin β3-mediated NF-κB signaling.
Since the tumor microenvironment plays important roles in cancer initiation, growth, progression, invasion and metastasis, it is possible to propose that an overexpression of IFNγ mRNA due to the pro-inflammatory microenvironment can lead to an up-regulation of CXCR4 mRNA and consequently to an increased TLR3 mRNA expression even among nodal negative patients.
Therefore, we introduced the complementary DNA (cDNA) encoding human IFNgamma into a well-characterized RCC line that has been selected for development of an allogeneic tumor cell vaccine for treatment of patients with metastatic disease.
Bone-marrow-derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice.
The latter included the melanoma cell line MeWo and its metastatic variant MeM 50-10, which display differential susceptibility to modulation of HLA class-II antigens by IFN-gamma and the cell lines SK-MEL-93-DX-2 and SK-MEL-93-DX-3, which originated from anatomically distinct metastases in patient DX.
The systemic injection of the CD40 ligand-expressing EPCs stimulated the secretion of both tumor necrosis factor-α and interferon-γ and increased the caspase 3/7 activity in the lungs with metastatic tumors, leading to prolonged survival of the tumor bearing mice.
NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation.
In the present study, 66 patients with gastric cancer were included; the expression level of Th1- and Th17-related IFN-γ, IL-17, T-bet, RORγt in gastric cancer tissues and peripheral blood mononuclear cell (PBMC) were detected, analyzed the relationship between Th17 or Th1 infiltration and metastasis and explored the possible mechanism.
In a multivariate analysis, patients with tumor depth >/=4 mm, IFG >/=8 points, and nodal metastasis had a reduced disease-free survival and IFG >/=11 points had a predictive value for nodal metastasis (odds ratio: 7.34; P = 0.0019).
The control of experimental metastases relied on the activation of host NK cells and IFNγ, while NK cells, CD8<sup>+</sup> T cells and IFNγ were needed for effective antitumor effect in the spontaneous metastases model.
We demonstrate that stronger secretion of CXCL10 (CXCR3 ligand) and CCL5 (CCR5 ligand) and infiltration of GzmB+CD8+ cytotoxic T-lymphocytes (CTLs) and IFN-γ+CD4+ helper T-cells can be predicted by transcriptional profiling, and that CRCs with stronger T-cell immunity were proportionally skewed towards early TNM stages and lacked distant organ metastasis.
Although it has been used clinically to treat a variety of malignancies, low levels of IFNγ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy.
We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNγ, granzyme B, and perforin production were recruited to the lung upon metastasis induction.
Although expression of huIL-2 was equally effective as IFN-gamma in preventing tumor formation and reducing experimental metastasis, it did not confer protection to spontaneous metastases and even reversed the anti-metastatic activity of IFN-gamma.