Abstract IA25: Immune cells promote metastasis and control dormancy
Authors: Toh Benjamin , Chew Valerie , Tham Muly , Abastado Jean-Pierre 
Published: August 2014

Abstract
While metastasis is the main cause of death by cancer, the nature, location and polarization of immune cells that infiltrate the primary tumor often constitute an independent predictor of cancer patient survival. In addition, several studies have shown that tumor-infiltrating immune cells correlate with clinical responses to treatments, including chemo-, radio- and targeted therapies. However, the underlying mechanisms of these correlations are still poorly understood. More efficient stratification of cancer patients based on immune cell infiltration could help in disease management and development of novel therapeutic strategies.
Using a spontaneous mouse model of uveal melanoma, we showed that myeloid-derived suppressor cells (MDSC) preferentially accumulate in the primary tumor under the influence of CXCR2 ligands. These MDSC are known to suppress the immune response. In addition, they provide growth and angiogenic factors which promote cancer cell proliferation. Our study showed that granulocytic MDSC also promote cancer cell dissemination and metastasis by inducing epithelial-mesenchymal transition (EMT) in cancer cells. Accordingly, depletion of MDSC reduces cancer cell dissemination and metastasis 1. This novel role of MDSC in promoting metastasis likely explains their negative effect on survival. Indeed, primary tumors infiltrated with granulocytic cells correlate with increased risk of metastasis, accelerated progression and shorter survival in several types of human cancer.
In the same mouse model, we observed that cancer cells start to disseminate at 3 weeks of age but macroscopic metastases only develop after 3-6 months. CD8+ T cells play a crucial role in controlling the dormancy of disseminated cancer cells since CD8+ T cell depletion accelerates the development of visceral metastases and shortens mouse survival. Surprisingly however, CD8+ T cell depletion has no effect on the development and growth of cutaneous metastases. In fact, CD8+ T cells poorly infiltrate cutaneous tumors. CD8+ T cell infiltration is regulated by chemokines, especially CXCR3 ligands and CCL5. By overexpressing these chemokines in cutaneous tumors, we were able to restore CD8+ T cell infiltration. We have identified several chemotherapeutic drugs that induce CXCR3 ligands and CCL5 expression in melanoma cell lines. Systemic treatment of tumor-bearing mice with these chemotherapies also induces intratumoral expression of these chemokines and promotes T cell infiltration into cutaneous tumors. Interestingly, in a cohort of melanoma patients treated with dacarbazine, T cell infiltration correlates with chemokine expression after chemotherapy. Moreover, chemotherapy augments chemokine expression and T cell infiltration only in chemotherapy-responsive tumors. Increased intratumoral expression of these chemokines after chemotherapy correlated with prolonged patient survival 2.
In patients with hepatocellular carcinoma, CXCR3 ligands and CCL5 also control T and NK cell infiltration. In this cancer however, pro-inflammatory cytokines and TLR ligands induce intratumoral expression of these chemokines.
Taken together, these data indicate that intratumoral chemokines control immune cell infiltration. Accordingly, different chemokines attract different types of immune cells, thereby shaping either a protective or a progressive environment. This network of chemokines and immune cells may be context-dependent and vary with the type of cancer and tumor location. Further identification of the signals that regulate chemokine expression in tumors may facilitate the prediction of disease evolution and response to therapy. Rational manipulation of these signals should help improve the efficacy of existing and future anti-cancer therapies.
1. Toh, B., et al. 2011. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9: e1001162.
2. Hong, M., et al. 2011. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 71: 6997-7009.
Citation Format: Benjamin Toh, Valerie Chew, Muly Tham, Jean-Pierre Abastado. Immune cells promote metastasis and control dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA25.