Presensitization of kidney-transplant recipients against MICA antigens is associated with an increased frequency of graft loss and might contribute to allograft loss among recipients who are well matched for HLA.

Immune checkpoint blockade therapy has been successful in treating some types of cancers but has not shown clinical benefits for treating leukemia 1 . This result suggests that leukemia exploits unique escape mechanisms. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukemia cells. It remains unknown whether these receptors can initiate immune-related primary signaling in tumor cells. Here we show that LILRB4, an ITIM-containing receptor and a monocytic leukemia marker, supports tumor cell infiltration into tissues and suppresses T cell activity via ApoE/LILRB4/SHP-2/uPAR/Arginase-1 signaling axis in acute myeloid leukemia (AML) cells. Blocking LILRB4 signaling using knockout and antagonistic antibody approaches impeded AML development. Thus, LILRB4 orchestrates tumor invasion pathways in monocytic leukemia cells by creating an immune-suppressive microenvironment. LILRB4 represents a compelling target for treatment of monocytic AML.

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Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types [1][2][3][4][5][6] . Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults [11][12][13] . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. RESULTSFasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14-22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25,26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation (Fig. 1a) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice (Fig. 1b,c). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks posttransplantation (Fig. 1c,d).Next, we measured the distribution of B lymphoblastic cells and myeloid cells in the GFP + compartment of the B-ALL mice. Control mice with B-ALL had 65-80% of B220 + cells (pan B lineage marker) and 0.5-2% of Mac-1 + cells (myeloid lineage marker) in GFP + fractions of PB, BM and SP (Fig. 1e,f), indicative of fully developed B-ALL. By contrast, there were only 19-28% of B220 + cells and 5-12% of Mac-1 + in GFP + fractions in fasted mice (Fig. 1e,f), consistent with loss of the B-ALL phenotype. There was also a higher percentage of New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered ...

The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P ‫؍‬ .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P ‫؍‬ .02) and HLA any mismatch (83% vs 46%, P ‫؍‬ .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P ‫؍‬ .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).