Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors
Regressions of metastatic solid tumors after allogeneic human leukocyte antigen (HLA)-matched stem cell transplantation (SCT) are often associated with detrimental graft-versus-host disease (GVHD). The graft-versus-host reaction of the HLA-matched donor is directed mainly against the multiple mismatched minor histocompatibility antigens (mHags) of the patient. mHags are strong HLA-restricted alloantigens with differential tissue distribution. Ubiquitously expressed mHags are the prime in situ targets of GVHD. The mHag HA-1 is hematopoiesis restricted, but displays additionally an aberrant expression on solid tumors. Thus, HA-1 might be an excellent target to boost the anti-solid tumor effect of allogeneic SCT without inducing severe GVHD. Here, we show that cytotoxic T lymphocytes (CTLs) solely targeting the human mHag HA-1 are capable of eradicating 3-dimensional human solid tumors in a highly mHagspecific manner in vitro, accompanied by interferon-γ release. In vivo, HA-1-specific CTLs distribute systemically and prevent human breast cancer metastases in immunodeficient mice. Moreover, HA-1-specific CTLs infiltrate and inhibit the progression of fully established metastases. Our study provides the first proof for the efficacy of a clinically applicable concept to exploit single mismatched mHags with hematopoiesisand solid tumorrestricted expression for boosting the anti-solid tumor effect of allogeneic SCT.
|Persistent URL||dx.doi.org/10.1182/blood-2007-11-125492, hdl.handle.net/1765/28868|
|Note||Free full text at PubMed|
Hambaeh, L, Vermeij, M, Buser, A, Aghai, Z, van der Kwast, Th.H, & Goulmy, E. (2008). Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors. Blood, 112(5), 1844–1852. doi:10.1182/blood-2007-11-125492