Malignant tumors maintain a dominant immunosuppressive microenvironment that facilitates their progression and dissemination, mediated by the secretion of soluble factors, recruitment of different subsets of immune cells and expression of immune-regulatory receptors. The immune-modulatory cytokine interleukin-12 (IL-12) is a promising alternative to overcome this suppressive microenvironment because of its direct role in the activation of innate and adaptive immunity and potent anti-angiogenic effect. Despite its potent activity in experimental models, the clinical use of IL-12 for the treatment of human cancers has proven difficult because of its toxicity.
The lung is a preferred site of metastasis for several types of tumor. Therefore, we hypothesized that local delivery of IL-12 could improve the immune response against lung metastases via modification of the tumor microenvironment and avoiding systemic toxicity. Therefore, we evaluated the anti-tumor activity of IL-12 in a murine model of metastatic B16 melanoma by intranasal delivery lentiviral vector encoding IL-12 (IL-12 LV).
This delivery route resulted in transduction of alveolar macrophages and a drastic reduction of lung metastases. Whilst treated mice survived longer than controls, they eventually succumbed to distant tumor lesions while their lungs remained tumor-free.
IL-12 LV treatment was associated with local infiltration and proliferation of effector subsets (NK, CD8+, CD4+ T cells) that expressed high levels of granzyme B and pro-inflammatory cytokines. These cells, however, are dispensable as IL12 LV was equally effective in models of NK and T cell ablation.
Interferon gamma (IFNγ) was identified as an essential cytokine in the mechanism of IL-12 LV mediated tumoricidal activity. IFNg expression under IL-12 LV treatment was observed in NK, T cell and Innate Like Cell (ILC) populations, the latter of which sufficiently sustains IFNγ dependant activity in the absence of NK and T cells.
The myeloid populations of the IL-12 LV treated lung were phenotyped and expansion of Interstitial Macrophages with high expression of MHC class II and inducible nitric oxide synthase (iNOS) was observed in an IFNγ dependant manner, therefore transgenic models of macrophage associated IFNγ insensitivity are currently being employed in order to elucidate the essential cytotoxic status of Interstitial Macrophages in models of IL12-LV mediated tumor rejection.
We conclude that activation of innate and adaptive immunity by local genetic delivery of IL-12 is effective for the treatment of metastatic melanoma in the lung. Despite its local effectiveness, systemic protection might require further combination therapy, such as vaccination or checkpoint inhibition.
Citation Format: Jake Y. Henry, Frederick Arce, Burkhard Becher, Karl S. Peggs, Sergio A. Quezada. Innate crosstalk between ILC and interstitial macrophages promotes lung cancer regression in response to IL-12 therapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A127.
- ©2016 American Association for Cancer Research.