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 mHag-specific manner in vitro, accompanied by interferon-gamma 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 hematopoiesis- and solid tumor-restricted expression for boosting the anti-solid tumor effect of allogeneic SCT.
Hambach
Lothar
L
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands. l.w.h.hambach@lumc.nl
Vermeij
Marcel
M
Buser
Andreas
A
Aghai
Zohara
Z
van der Kwast
Theodorus
T
Goulmy
Els
E
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020350:Graft vs Tumor Effect; D006801:Humans; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009842:Oligopeptides / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
C110615:HA-1 antigen; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides