In the Spotlight...

Elimination of tumor by CD47/PD-L1 dual-targeting fusion protein that engages innate and adaptive immune responses

Building on prior evidence that anti-PD-1 and anti-CD47 antibodies can synergize by stimulating both the innate and adaptive immune systems and that tumor cells co-express both targets, Liu et al. developed a bispecific antibody (IAB) targeting both molecules. In vitro, IAB promoted T cell activation and macrophage phagocytosis. In an immunocompetent MC38 mouse model, intratumoral injection of IAB led to partial or complete antitumor responses in most mice. Both CD8+ T cells and macrophages contributed to the anti-tumor effect of IAB.

Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy

Barkal et al. discovered that a high level of expression of MHC class I molecules on the surface of tumor cells provides protection against phagocytosis by macrophages, mediated by interaction between the LILRB1 inhibitory receptor on the surface of macrophages and the β2-microglobulin component of the MHC class I molecule, independent of the MHC-I allele. Disrupting the MHC class I/LILRB1 axis, similar to disruption of the CD47/SIRPα axis, enhances phagocytosis of tumor cells in vitro and in vivo.

STAT5B: A Differential Regulator of the Life and Death of CD4(+) Effector Memory T Cells

To understand the mechanism underlying antigen restimulation-induced T cell death (RICD), a critical control to dampen T cell effector memory (TEM) levels, Majri et al. observed that STAT5B signaling drives RICD in TEM cells. A genetic screen of a patient with an autoimmune disorder revealed a missense mutation in the dimerization domain of STAT5B, causing lack of transcriptional activity. The patient’s CD4+ TEM cells were significantly increased and were highly resistant to cell death by in vitro TCR restimulation.

Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments

To reduce systemic side effects of alpha interferon but retain immune cell stimulating activity, Cauwels et al. constructed a mutated cytokine with >100x lower potency targeted to Clec9A+ cross-presenting dendritic cells (Clec9A-mAFN). In vivo, peri-tumoral Clec9A-mAFN stimulated Clec9A+ DCs in tumor-draining lymph nodes, controlled tumor growth in multiple models as well as full strength interferon but without toxicity, and synergized with other therapies, including checkpoint blockade. Activity depended on Batf3+ DCs and CD8+ T cells.

TEM8/ANTXR1-specific CAR T cells as a targeted therapy for triple-negative breast cancer

Byrd et al. engineered CAR T cells targeting TEM8, a marker on triple-negative breast cancer (TNBC), breast cancer stem-like cells (BCSCs), and tumor endothelial cells (TEC). The CAR T cells effectively killed TEC and TNBC cells and reduced the formation of mammospheres by BCSCs in vitro. In vivo, the CAR T cells induced regression of established cell line- and patient-derived xenograft tumors, disrupted tumor vascularization and infrastructure, blocked metastasis in xenograft tumors derived from a lung metastatic TNBC cell line, and improved survival.

An Efficient Single-Cell RNA-Seq Approach to Identify Neoantigen-Specific T Cell Receptors

Lu et al. developed a new approach to identify neoantigen-specific TCRs for use in adoptive T cell transfer. The process involves briefly co-culturing expanded tumor-infiltrating lymphocytes with autologous APCs that have been transfected with tandem minigenes containing patient-specific mutations or pulsed with mutant peptide, and using single-cell RNA sequencing to identify TCR sequences on activated T cells that express high levels of IFNγ and/or IL-2. A clinical trial to test this approach is being planned.

Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells

Sethumadhavan et al. discovered that hypoxia in the tumor microenvironment, and in 3D cultures, leads to decreased surface expression of MHC class I molecules by downregulating transcription of MHC class I heavy chains via the hypoxia-inducible factor (HIF) and by decreasing the levels of TAP1, TAP2, and LMP7, critical components of the antigen processing pathway. These results suggest that cancer immunotherapy may be improved by the addition of oxygenation or HIF inhibition.

Anti-SIRPalpha antibody immunotherapy enhances neutrophil and macrophage antitumor activity

Ring et al. developed KWAR23, an antibody that targets the SIRPα receptor on myeloid cells, to disrupt binding to the CD47 “don’t eat me” signal expressed on tumor (and normal) tissue to prevent macrophage phagocytosis. In combination with tumor-opsonizing antibodies, KWAR23 induced macrophages and neutrophils to phagocytose target tumor cells (from various tumor cell lines) in vitro. In human sirpa knock-in mice on an SRG background (lacking T, B, and NK cells), this combination elicited partial and complete responses.

Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response

Xue et al. used a single-cell microfluidics device to simultaneously measure 16 cytokines released by CD19 CAR T cells in response to target-specific stimulation, and developed two novel bioinformatics tools to visualize the data. CD19 CAR T cells exhibited a high degree of polyfunctionality (production of multiple cytokines, a predictor of therapeutic efficacy) dominated by antitumor effector and stimulatory functions, and significant heterogeneity, both within cells from the same donor and between donors.

PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

In T cell non-Hodgkin lymphoma (NHL), oncogenic mutations to the TCR pathway induce chronic proliferation, however, Wartewig et al. found that PD-1 receptor-driven T cell inhibition suppresses oncogenic signaling in premalignant cells. In this context, total or hemizygous knockout of the PD-1 gene led to T cell hyperproliferation and rapid lymphomagenesis; treatment with anti-PD-1 antibodies led to lethal hyperproliferation, but the expanded cells were not lymphomagenic. Caution is warranted in employing checkpoint inhibition in T cell NHL.

Previous Digests

How our genes let the tumors get away

November 29, 2017

How does the immune system sculpt the tumor genome even before the tumor adapts counteracting immune evasion mechanisms? Marty et al. hypothesized that antigenic oncogenic mutations are eliminated by the immune system in the early stages of tumorigenesis, and this process is dependent on which oncogenic peptides can be effectively presented by an...

What’s in your gut? The gut microbiome influences the efficacy of anti-PD-1 immunotherapy

November 22, 2017

Responses to immunotherapy vary due to a number of factors, and according to two recent papers published in Science, the gut microbiome is definitely one of them. Both papers indicated that diversity of bacteria and the abundance of certain types of bacteria can affect patients’ response to anti-PD-1 immunotherapy for some cancer types...

What’s keeping natural killer cells in check?

November 15, 2017

In a recent paper published in Nature, Molgora et al. demonstrated that interleukin-1 receptor 8 (IL-1R8), which is a negative regulator of the IL-1 receptor (ILR) and Toll-like receptor (TLR) pathways, acts as a checkpoint for natural killer (NK) cell maturation and function, and removing this checkpoint could affect tumorigenesis and metastasis. Although...

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