Differential Immune Susceptibility of Malignant Versus Normal Tissue Leads to Tumor Rejection without GVH after Adoptive Immunotherapy.
Authors: Delisle Jean-Sebastien , Meunier Marie-Christine , Barron Chantal , Bergeron Julie , Perreault Claude 
Published: April 2020

Abstract
Adoptive immunotherapy based on the injection of allogenic cytotoxic T-lymphocytes (CTL) during or after bone marrow transplant (BMT) has established itself as a potent anti-neoplastic treatment for several malignancies. However this approach is limited by the occurence of graft versus host disease (GVH). Using a previously described murine adoptive immunotherapy model where donor and recipient are mismatched for a single dominant minor histocompatibility antigen (H7a), and where a powerful anti-neoplastic effect is seen without GVH, we sought to determine what rendered cancer cells more vulnerable than normal cells to immune attack. B10.H7a mice were lethally irradiated and reconstituted with B10.H7b (H7a negative) T-depleted bone marrow. On the day of transplant, these mice received a B16.F10 (H7a positive) melanoma challenge. Adoptive transfer of splenocytes obtained from B10.H7b mice previously immunized with B10.H7a splenocytes was performed on day 7 post BMT. Following transfer of those splenocytes containing primed anti-H7a CTL, neither GVH nor vitiligo was noted in recipients despite the fact that H7a is expressed in all tissues and organs. 50% of treated mice, versus 0% of controls rejected the tumor and survived 100 days. Overall survival was increased to 80% when adoptive transfer was carried on day 3 post BMT. The injection of anti-H7b CTL had no effect on melanoma growth. Thus, the anti-tumor activity was T-cell receptor recognition dependent and not a mere bystander effect. In treated mice but not in controls, tumor histology and flow cytometry revealed important CTL infiltration (80% of those CTL being MHC-H7a tetramer positive), increased expression of MHC class I molecules (MHC I) at melanoma cell surface, expression of Rae-1 (an NKG2D ligand), tumor necrosis and decreased angiogenesis. Importantly, normal skin in treated or control animals showed no increased expression of MHC I or Rae-1. B16.F10 melanoma cells express almost no MHC I, and no Rae-1 when cultured in vitro. Co-incubation of B16.F10 cells with INFγ leads to increased MHC I expression but no induction of Rae-1 expression, implying that at least a second factor is present in vivo to account for the expression of this stress ligand. An additional role for INFγ was evidenced when anti-H7a CTL were injected in INFγ receptor knock-out recipients. The angiostatic effect noted after anti-H7a CTL injection was abrogated and no mice were cured. Thus, INFγ-mediated angiostasis on the tumor stroma was crucial for the inhibition of cancer progression.
Conclusion: in our model, the differential immune susceptibility of tumor versus normal cells appears to stem from the fact that neoplastic cells are induced to express more MHC I and stress ligands such as Rae-1. Those can respectively increase target antigen density at the cell surface and mediate CTL co-stimulation or cytotoxicity, through NKG2D receptors. Strategies exploiting stress ligand induction as well as the effect of INFγ on MHC expression and angiostasis may contribute to successfully separate anti-tumor from GVH effects.