Editors' ChoiceCancer

Tumors Vent Their Spleen

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Science Translational Medicine  10 Oct 2012:
Vol. 4, Issue 155, pp. 155ec184
DOI: 10.1126/scitranslmed.3005078

The immune system is geared to maintain the status quo: It attacks dangerous invaders but leaves healthy tissue alone. Tumors are like wolves in sheep’s clothing—they con the immune response into treating them like healthy tissue through a process called tolerance induction. Much remains to be understood about how or where tumors induce immune tolerance. Now, Ugel et al. report that tolerance may be induced remotely in the spleen rather than in the lymph nodes nearest the tumor.

The spleen is an organ with many functions, including production and removal of blood cells and stimulation of immune responses (in the red and white pulp, respectively). The authors show that, in tumor-bearing mice, systemic tolerization of CD8+ killer T cells happens—surprisingly—not in the tumor-draining lymph node but in the red pulp of the spleen. These cells responsible for tolerance induction are mostly monocytes and their immature precursors. Indeed, transferring tumor antigen–specific CD8+ T cells into mice that had their spleens removed led to a significant increase in survival compared with mice subjected to sham surgery. However, removing the spleen is not the ideal therapy in the clinic. Thus, the authors targeted splenic antigen-presenting cells with chemotherapy and found that transferred tumor-specific killer T cells led to tumor regression. A similar phenotype was observed in MCP-1– and CCR2-deficient mice, suggesting that this cytokine axis regulates presence of antigen-presenting inflammatory monocytes in the spleen. To explore the clinical relevance of the mouse data, the authors studied patients with renal and colorectal cancer who received therapeutic vaccines. In these patients, blood MCP-1 levels correlated positively with the expansion of circulating immature myeloid cells. High MCP-1 serum levels predicted an impaired response to immunotherapy and a worse prognosis.

These findings indicate that the tumor hijacks the spleen to instruct the body's immune defense to “stand down” and highlight the potential of the chemokine receptor CCR2 as a therapeutic target.

S. Ugel et al., Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep. 2, 628–639 (2012). [Full Text]

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