Systemic T-cell and humoral responses against cancer testis antigens in hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide due to high recurrence rates after curative treatment and being frequently diagnosed at an advanced stage. Immune-checkpoint inhibition (ICPI) has yielded impressive clinical successes in a variety of solid cancers, however results in treatment of HCC have been modest. Vaccination could be a promising treatment to synergize with ICPI and enhance response rates.

Current Tolerance-Associated Peripheral Blood Gene Expression Profiles After Liver Transplantation Are Influenced by Immunosuppressive Drugs and Prior Cytomegalovirus Infection.

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplant (LTx) recipients weaned off immunosuppressive drugs (IS). Several previous studies have investigated whether peripheral blood gene expression profiles could identify operational tolerance in LTx recipients. However, the reported gene expression profiles differed greatly amongst studies, which could be caused by inadequate matching of clinical parameters of study groups.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1 tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells.

Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma.

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis.

Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma.

Background And Aims: Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients.

Methods: Twenty-six mostly advanced HCC patients were enrolled.

TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8 T Cells in Hepatocellular Carcinoma.

Background & Aims: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs).

The biological process of lysine-tRNA charging is therapeutically targetable in liver cancer.

Background & Aims: Mature transfer RNAs (tRNA) charged with amino acids decode mRNA to synthesize proteins. Dysregulation of translational machineries has a fundamental impact on cancer biology. This study aims to map the tRNAome landscape in liver cancer patients and to explore potential therapeutic targets at the interface of charging amino acid with tRNA.

Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance.

Background & Aims: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment.

Methods: Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors.

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells.

Background: OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials.

Methods: Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds.

LGR5 marks targetable tumor-initiating cells in mouse liver cancer.

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma.

Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules.

Background & Aims: Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody therapy is unknown, and knowledge of its tumor immune microenvironment is limited. We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma and assess functional effects of targeting checkpoint molecules on TILs.

GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma.

No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti-PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co-inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co-stimulatory receptors might be able to stimulate anti-tumor immunity in HCC is as yet unknown.

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy.

: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. : The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer.

: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). : Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC.

Spatially resolved observation of dipole-dipole interaction between Rydberg atoms.

We have observed resonant energy transfer between cold Rydberg atoms in spatially separated cylinders. Resonant dipole-dipole coupling excites the 49s atoms in one cylinder to the 49p state while the 41d atoms in the second cylinder are transferred down to the 42p state. We have measured the production of the 49p state as a function of separation of the cylinders (0-80 microm) and the interaction time (0-25 micros).

Streak camera operating in the mid infrared.

An atomic streak camera has been constructed that operates from the near to the far infrared. The photocathode used in conventional streak cameras for the conversion of photons to electrons has been replaced by gas-phase atoms in a Rydberg state. The low binding energy of the electron in a Rydberg atom combined with the large photoionization cross section of a Rydberg atom makes Rydberg atoms suitable for use in an infrared streak camera.

Atomic spectral detection of tunable extreme ultraviolet pulses.

A novel method of detecting the spectral width and wavelength of extreme ultraviolet (XUV) pulses with a minimum number of experimental tools is demonstrated. The method relies on the photoionization probability of an atom as a function of the electric field. A tunable laser source in the XUV is used that is based on higher-harmonic generation of the frequency-doubled output of a 50-fs Ti:sapphire laser.

Programmable nanolithography with plasmon nanoparticle arrays.

We describe how optical contact lithography based on plasmon particle array masks allows generation of a large number of different subwavelength exposure patterns using a single mask. Within an exact point dipole model, we study the local response of silver particles in small two-dimensional arrays with 50-200 nm spacing. We show how illumination with unfocused light allows optically addressing particles either individually or in controlled configurations; which pattern will be exposed by the mask is programmed by varying the wavelength, incidence angle, and polarization of the incident wave.

Asymmetric response in a line of optically driven metallic nanospheres.

We describe the dipole-dipole interactions between a linear array of optically driven silver metallic nanospheres (MNSs). These model calculations incorporate the full electric field generated by an oscillating dipole and predict several interesting effects due to the retardation of the field. The distribution of the power associated with MNSs along the array shows a strong variation on a scale smaller than the wavelength of the driving light.

Control of atomic ionization by two-color few-cycle pulses.

We have studied the ionization of Rydberg atoms by few-cycle radio-frequency pulses and used two-color fields to control the ionization dynamics. We show that the number of times that electrons are emitted during a pulse can be limited and that the duration of the electron emission can be shortened. These results, once they are transposed to the optical domain, may inspire new strategies for the production of single attosecond pulses.

Carrier phase dependence in the ionization of Rydberg atoms by short radio-frequency pulses: a model system for high order harmonic generation.

We report time-resolved electron emission in experiments on ionization of rubidium Rydberg atoms (n=90) by few-cycle radio-frequency (RF) (1-10 MHz) pulses. The electron emission occurs in multiple bursts and strongly depends on the carrier-envelope phase as well as the duration and amplitude of the RF pulses. Remarkably, ionization is observed during a series of cycles with the same amplitude.

Asymmetry in the strong-field ionization of Rydberg atoms by few-cycle pulses.

We present measurements of the electron ejection direction in the ionization of high (n=90) Rydberg states of rubidium subjected to few-cycle radio-frequency (RF) pulses. For weak pulses we find a strong asymmetry for even (cosine) pulses and no asymmetry for odd (sine) pulses. This asymmetry disappears for pulses longer than four RF cycles.

Rydberg state ionization by half-cycle-pulse excitation: strong kicks create slow electrons.

The asymptotic velocity distribution of electrons ionized in half-cycle-pulse excitation of high Rydberg states (n=34), placed in a static electric field, is studied using electron velocity-map imaging. At weak half-cycle pulse strengths, the electrons escape over the saddle point in the potential. For strong half-cycle pulses, the electrons are emitted in the direction of the field kick.

Displacing Rydberg electrons: the mono-cycle nature of half-cycle pulses.

A THz "half-cycle" pulse is a fast ( <1 ps) unipolar pulse, followed by a slow unipolar pulse of opposite polarity. We found that the interaction of such THz pulses with very high Rydberg states results in a displacement of the electron within the atom, while the ionization is strongly suppressed. In classical terms: the first fast unipolar feature corresponds to a start kick of the Rydberg electron, while the second unipolar feature acts as a stop kick.

Static and dynamic transport of light close to the Anderson localization transition.

Anderson localization of light refers to an inhibition of wave transport in scattering media due to the interference of multiple scattered waves. We present wavelength dependent midinfrared optical transport measurements in slabs of randomly packed germanium (Ge) micron-sized particles, using a free electron laser as a tunable source of pulsed radiation. Because of their high refractive index and low absorption, Ge and similar semiconductors are excellent systems to study Anderson localization of light.