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.
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.
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.
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.
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.
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.
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.
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.