Effect of External Beam Radiation Therapy and Brachytherapy on Circulating Myeloid-Derived Suppressor Cell Populations in Patients Treated Definitively for Cervical Cancer.

Purpose: The immunosuppressive function of myeloid-derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer and is associated with poor prognosis. Radiation treatment is known to alter immune cell populations within the tumor; however, whether this results in the recruitment of immunosuppressive MDSC populations is not well understood. Here we evaluate the response of circulating MDSC populations in patients treated per standard-of-care cisplatin chemoradiation therapy (CRT) for locally invasive cervical cancer.

The ATP-exporting channel Pannexin 1 promotes CD8 T cell effector and memory responses.

Sensing of extracellular ATP (eATP) controls CD8 T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin 1 (Panx1). Whether Panx1 controls CD8 T cell immune responses , however, has not been previously addressed.

Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8 T cells.

Interleukin-7 (IL-7) is considered a critical regulator of memory CD8 T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (T) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that loss had only a modest effect on persistence of circulating memory and T subsets and that IL-7Rα was primarily required for normal basal proliferation.

The ATP-exporting channel Pannexin-1 promotes CD8 T cell effector and memory responses.

Sensing of extracellular ATP (eATP) controls CD8 T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8 T cell immune responses , however, has not been previously addressed.

Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8 T cell subsets.

Interleukin-15 (IL-15) is often considered a central regulator of memory CD8 T cells, based primarily on studies of recirculating subsets. However, recent work identified IL-15-independent CD8 T cell memory populations, including tissue-resident memory CD8 T cells (T) in some nonlymphoid tissues (NLTs). Whether this reflects the existence of IL-15-insensitive memory CD8 T cells is unclear.

P2RX7 Enhances Tumor Control by CD8+ T Cells in Adoptive Cell Therapy.

Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes the generation of memory populations following acute infections. However, data suggest that P2RX7 may limit the efficacy of antitumor responses. Herein, we show that P2RX7 is beneficial for optimal melanoma control in a mouse CD8+ T-cell adoptive transfer model.

The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8 T Cells.

Development of CD8 central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8 T cells display heterogeneous expression of the extracellular ATP sensor P2RX7.

Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8 tissue-resident memory T cells.

Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8 tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos CD8 T cells exhibited defective Trm generation but produced recirculating memory populations normally.

Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8 Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β.

Tissue-resident memory (Trm) CD8 T cells mediate protective immunity in barrier tissues, but the cues promoting Trm cell generation are poorly understood. Sensing of extracellular adenosine triphosphate (eATP) by the purinergic receptor P2RX7 is needed for recirculating CD8 T cell memory, but its role for Trm cells is unclear. Here we showed that P2RX7 supported Trm cell generation by enhancing CD8 T cell sensing of TGF-β, which was necessary for tissue residency.

Self-Regulation of Memory CD8 T Cell Metabolism through Extracellular ATP Signaling.

Following activation, CD8 T cells transition from reliance on mitochondrial respiration to increasing utilization of aerobic glycolysis. After the effector phase, however, reversion to mitochondrial metabolism is pivotal generating memory CD8 T cells. We recently showed that sensing of extracellular ATP (eATP) through the receptor P2RX7 is crucial for both production and the long-term survival of memory CD8 T cells, evidently through promoting mitochondrial maintenance.

TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance.

Chimeric antigen receptor (CAR)-expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non-major histocompatibility complex-restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined.

Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase.

We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells.

4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy.

Preparation, crystallization, and preliminary crystallographic analysis of wild-type and mutant human TREM-2 ectodomains linked to neurodegenerative and inflammatory diseases.

TREM-2 (triggering receptor expressed on myeloid cells-2) is an innate immune receptor expressed on dendritic cells, macrophages, osteoclasts, and microglia. Recent genetic studies have reported the occurrence of point mutations in TREM-2 that correlate with a dramatically increased risk for the development of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. Structural and biophysical studies of wild-type and mutant TREM-2 ectodomains are required to understand the functional consequences of these mutations.