Editors' ChoiceCancer Immunology

LIGHTing up the tumor microenvironment

Sci. Signal.  22 Mar 2016:
Vol. 9, Issue 420, pp. ec65
DOI: 10.1126/scisignal.aaf7133

Immune cells can recognize and attack tumor cells. However, various aspects of a tumor interfere with this response. Two studies have found ways to potentially overcome these barriers. Antibodies blocking the suppressive T cell checkpoint interaction between programmed cell death protein 1 (PD-1) on T cells and its ligand (PD-L1) on tumor cells (anti–PD-L1 therapy) is effective in some patients but often requires combination with other checkpoint-targeted therapies to increase its efficacy and, still, some tumors are unresponsive. Tang et al. found that the amount of T cell infiltration, but not PD-L1 abundance, determined the response of tumors to anti–PD-L1 therapy. To increase lymphocyte infiltration in therapy-resistant tumors, the authors designed antibodies that fused LIGHT, a ligand for the lymphotoxin β receptor (LβTR) on stroma cells, to an antibody against a protein on the surface of tumor cells [in this case, epidermal growth factor receptor (EGFR)]. LIGHT-fusion antibodies stimulated the abundance of inflammatory cytokines in tumor homogenates, and this positively correlated with increased abundance of infiltrating lymphocytes. However, the LIGHT-fusion antibody also increased the abundance of PD-L1 on the tumor cell surface, making it ineffective as a single-agent therapy. Combining the LIGHT-fusion antibody with the PD-L1 antibody eradicated established mouse and human tumors in immune-competent or immune-reconstituted mice, respectively, and enabled mice to reject subsequently injected tumor cells.

In addition to signals from the tumor cells themselves, the often nutrient- and oxygen-poor nature of the tumor microenvironment affects immune cell proliferation, differentiation, and metabolism (see a Review by Thurnher and Gruenbacher in Science Signaling), which alters their activity. The cytokine-responsive protein STAT3 promotes the proliferation and differentiation of myeloid-derived suppressor cells (MDSCs), an immune cell type associated with tumor progression. Increased activity or abundance of STAT3 is also often observed in tumor cells, thus, targeting STAT3 is an attractive option to target tumors and MDSCs. Unfortunately, although STAT3 inhibitors suppress tumor cell proliferation in culture and reduce MDSC populations in the spleen; they have not been an effective anticancer therapy in the clinic. Kumar et al. found that STAT3 activity in MDSCs is suppressed by a hypoxic tumor microenvironment. After ruling out the typical hypoxia-regulated factors, the authors found that hypoxia increased the activity of CD45 protein tyrosine phosphatase (CD45PTP) in MDSCs by increasing the sialylation of CD45PTP monomers and thereby preventing their dimerization (a less active form). Knocking down CD45PTP or using sialidase, which degrades sialic acid, prevented hypoxia-induced suppression of STAT3 phosphorylation in cultured MDSCs. Sialidase treatment alone enhanced the growth of tumors in mice and increased the number of tumor-associated MDSCs, which could be interpreted that sialidase should not be a component of therapy. However, combining sialidase with STAT3 inhibitors prevented the growth of typically STAT3 inhibitor-resistant sarcoma in mice, and tumor-associated MDSCs were undetectable after the combination treatment. This suggests that increasing the dependency of the MDSCs on STAT3 sensitizes these cells to the effects of STAT3 inhibitors, enabling the cytotoxic cells of the immune system to target the tumor. The studies identify new ways to improve immunotherapy-based strategies in cancer patients.

H. Tang, Y. Wang, L. K. Chlewicki, Y. Zhang, J. Guo, W. Liang, J. Wang, X. Wang, Y.-X. Fu, Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29, 285–296 (2016). [PubMed]

V. Kumar, P. Cheng, T. Condamine, S. Mony, L. R. Languino, J. C. McCaffrey, N. Hockstein, M. Guarino, G. Masters, E. Penman, F. Denstman, X. Xu, D. C. Altieri, H. Du, C. Yan, D. I. Gabrilovich, CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44, 303–315 (2016). [PubMed]

M. Thurnher, G. Gruenbacher, T lymphocyte regulation by mevalonate metabolism. Sci. Signal. 8, re4 (2015). [Abstract]