Miranda P. Dierselhuis

Anakinra is an effective treatment for flares in PAPA syndrome.

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

PURPOSE OF REVIEW: Disparities in minor histocompatibility antigens between HLA-matched organ and hematopoietic stem cell donors and recipients create the risks of graft failure and graft-versus-host disease (GvHD) respectively. A decade ago, technical advances combined with genomic information resulted in the identification of the chemical nature of the first series of minor histocompatibility antigens, facilitating their molecular typing. A new era of research had begun in exploring the role of minor histocompatibility antigens in physiological and nonphysiological settings. Here we summarize, to the best of our knowledge, human studies on the relevance of minor histocompatibility antigens in solid organ transplantation with a main focus on renal allografting. RECENT FINDINGS: The minor histocompatibility antigen HY is associated with acute rejection, and male grafts in female recipients have reduced graft survival; both cellular and humoral responses are observed. Studies on autosomal minor histocompatibility antigens on graft rejection are less conclusive; their role in transplant tolerance, however, offers perspective. SUMMARY: Information on the clinical relevance of minor histocompatibility antigen allo-immune responses in solid organ allografting is still scarce. The possible implications of the minor histocompatibility allo-immune responses for future clinical practice in solid organ transplantation are discussed in relation to their possible detrimental or beneficial effects on the host.