Solid Tumor–Induced Immune Regulation Alters the GvHD/GvT Paradigm after Allogenic Bone Marrow Transplantation

Abstract

Growth of solid tumors is often associated with the development of an immunosuppressive tumor microenvironment (TME). It has been suggested that the influence of the TME may extend beyond the local tumor and results in systemic immunosuppression. Here, we utilize two murine cancer models to explore the influence of solid tumors on the occurrence of alloreactivity-driven GvHD and graft-versus-solid tumor (GvT) effects following MHC-mismatched allogeneic bone marrow transplantation (allo-BMT). Melanoma-or colon carcinoma-bearing C57BL/6 mice did not develop GvHD after BMT even when the bone marrow inoculum was supplemented with donor-type splenocytes. This protection against GvHD required the presence of tumors because its resection prior to allo-BMT promptly resulted in development of GvHD. In addition, tumor-bearing mice given T-cell-depleted allo-BMT (allo-TCD-BMT) failed to develop GvHD and also showed significantly stronger GvT effects than mice given allo-BMT. The GvT effects in allo-TCD-BMT recipients were associated with profound changes in tumor-infiltrating cells compared with that in allo-BMT recipients, with significantly reduced donor-derived regulatory T cells (Treg), increased cytotoxic effector (IFNg hi ) CD8 T cells, and increased M1 macrophages (iNOS hi , arginase lo , and IL10 lo ); the use of macrophage-depleted bone marrow abrogated the GvT effects. Collectively, these results indicate that the presence of M1 macrophages may disrupt the generation of donor-type Treg cells so that the immunomodulatory effect of the TME can affect systemic immunity.Significance: These findings show that cells such as T cells or macrophages in the bone marrow inoculum may interfere with the systemic and local immune reactivity against tumors.

Improved Anti-Tumour Adaptive Immunity Can Overcome the Melanoma Immunosuppressive Tumour Microenvironment

“…One of the major factors hindering current cancer immunotherapies is the TME that impedes the anti-cancer adaptive immune response [1,2,3]. Previous work from our group demonstrated that the TME extends beyond the tumour and can result in systemic immunosuppression [5]. Hence, there is an urgent need to better understand the features of TME and to develop new therapeutic strategies to overcome the TME [4,5,6].…”

“…Before the harvesting of B16 cells, a trypsin–EDTA solution was added to the culture flask for 5 min at 37 °C in a 5% CO 2 to detach the tumour cells. Prior to their use, cells were tested for the presence of endotoxins with the LAL Chromogenic Endotoxin Quantitation Kit (Pierce) and for mycoplasma with PlasmoTest (InvivoGen) [5].…”

“…Direct immunofluorescence using the following antibodies CD3, CD4, H-2K b and H-2K d (eBioscience) was performed as previously described [5]. Intracellular staining for Foxp3 (FJK-16s) was performed using the Foxp3 Transcription Factor Staining Buffer Set according the manufacturer’s instructions (eBioscience).…”

“…Active immunosurveillance and elimination of malignant cells are central in the prevention of cancer development by the immune system. Tumour cells evade anti-tumour immunity via a process known as immune-editing [1,2,3] and the growth of solid tumours is often associated with the development of an immunosuppressive tumour microenvironment (TME) [4,5]. The development of metastases is consistently associated with a poor prognosis and remain the major cause of morbidity and mortality related to cancer in the clinic [5,6].…”

“…Tumour cells evade anti-tumour immunity via a process known as immune-editing [1,2,3] and the growth of solid tumours is often associated with the development of an immunosuppressive tumour microenvironment (TME) [4,5]. The development of metastases is consistently associated with a poor prognosis and remain the major cause of morbidity and mortality related to cancer in the clinic [5,6]. The TME consists of complex cellular and soluble components including not only malignant cells but also tumour infiltrating immune cells such as immune regulatory cells (e.g., Tregs) and tumour cell surrounding stromal cells [4].…”