Targeting tumor stroma to prevent cancer escape

Michael Spiotto, Donald A. Rowley and Hans Schreiber

Department of Pathology and the Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA

*email: hszz@midway.uchicago.edu

Solid tumors represent the vast majority of human cancers. Most of these cancers have been present in the patients for a considerable length of time (many weeks, months or even years) before they are clinically detected. Such solid tumors are well embedded in normal host tissues, so-called tumor stroma, that helps these cancers to grow while preventing an effective immune attack. Either these cancers are ignored by, or cause tolerance of, the host's immune system; and even when it is effective to kill most of the cancer cells, some of them escape as resistant variants, re-grow and kill the host. Because of the enormous genetic instability of cancers, such variants are regularly present. Therefore, in humans and equally in experimental animals, there are considerable difficulties to eradicate cancers once they are firmly established in the host. We have found the conditions that allow complete rejection of well-established solid tumors in mice, and think similar approaches will also be effective in human cancer. The key to success is to force recognition across the stromal barrier and to achieve stromal destruction. This not only leads to the elimination of most of the cancer cells but also to the elimination of a smaller, nevertheless critical population of cancer cells, i.e., the heritable escape variants. Thus, we find that destruction of these variants by stromal targeting prevents lethal relapse.

This work was supported by National Institutes of Health grants RO1-CA22677, RO1-CA37516, and PO1-CA97296, a Designated Grant from the Cancer Research Institute, and University of Chicago Cancer Research Center CA-14599. MTS is a recipient of the training grant HD 07009.