Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

Acute myeloid leukemia (AML) remains an elusive disease to treat, let alone cure, even after highly intensive therapies such as stem cell transplants. Adoptive cell therapeutic strategies based on conventional alpha beta (αβ)T cells are an active area of research in myeloid neoplasms given their remarkable success in other hematologic malignancies, particularly B-cell-derived acute lymphoid leukemia, myeloma, and lymphomas. Several limitations have hindered clinical application of adoptive cell therapies in AML including lack of leukemia-specific antigens, on-target-off-leukemic toxicity, immunosuppressive microenvironments, and leukemic stem cell populations elusive to immune recognition and destruction. While there are promising T cell-based therapies including chimeric antigen receptor (CAR)-T designs under development, other cytotoxic lymphocyte cell subsets have unique phenotypes and capabilities that might be of additional benefit in AML treatment. Of particular interest are the natural killer (NK) and unconventional T cells known as invariant natural killer T (iNKT) and gamma delta (γδ) T cells. NK, iNKT, and γδT cells exhibit intrinsic anti-malignant properties, potential for alloreactivity, and human leukocyte-antigen (HLA)-independent function. Here we review the biology of each of these unconventional cytotoxic lymphocyte cell types and compare and contrast their strengths and limitations as the basis for adoptive cell therapies for AML

Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis

NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann–Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target