Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity.

T cell surface CTLA4 sequesters the costimulatory ligands CD80 and CD86 on antigen-presenting cells (APCs) to prevent autoimmunity. Therapeutic immunosuppression by recombinant CTLA4-immunoglobulin (Ig) fusion proteins, including abatacept, is also attributed to CD80/CD86 blockade. Recent studies show that CTLA4-Ig binding to APC surface cis-CD80:PD-L1 complexes can release the inhibitory ligand PD-L1, but whether this contributes to T cell inhibition remains unclear.

The complexity of immune evasion mechanisms throughout the metastatic cascade.

Metastasis, the spread of cancer from a primary site to distant organs, is an important challenge in oncology. This Review explores the complexities of immune escape mechanisms used throughout the metastatic cascade to promote tumor cell dissemination and affect organotropism. Specifically, we focus on adaptive plasticity of disseminated epithelial tumor cells to understand how they undergo phenotypic transitions to survive microenvironmental conditions encountered during metastasis.

Estrogen-induced immune changes within the normal mammary gland.

Breast cancer (BCa) incidence increases following aberrant hormone exposure, which has been linked to direct effects on estrogen receptor (ER) mammary epithelium. While estrogen exposure during mammary involution has been shown to drive tumour growth via neutrophils, the potential for the ER + immune microenvironment to mediate part (in addition to mammary epithelial cells) of hormonally controlled BCa risk during normal development has not been assessed. We collected mammary tissue, lymph nodes and blood from tumour naïve mice treated with, oophorectomy, estrogen (17β estradiol) or Fulvestrant.

Basic cancer immunology for radiation oncologists.

Although the impressive clinical responses seen with modern cancer immunotherapy are currently limited to a subset of patients, the underlying paradigm shift has resulted in now hardly a segment in oncology that has not been touched by the immuno-oncology revolution. A growing body of data indicates that radiation therapy (RT) can modulate the tumour immune microenvironment and complement cancer immunotherapy via non-overlapping mechanisms to reinvigorate immunity against cancer. Thus, increasingly RT is viewed as a highly unique partner for immunotherapy across the spectrum of cancer settings, as radiobiology and cancer immunology foreseeably become more intertwined.

CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors.

Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy.

Literature Review of Sex Differences in mTBI.

Introduction: Traumatic brain injury (TBI) remains a significant source of morbidity worldwide and is of particular concern for the military. Scientific literature examining sex differences in TBI is highly contradictory with some reporting better outcomes in men, others reporting better outcomes in women, and others reporting mixed results or no difference. While the exact cause is currently debated, the existence of such differences has important implications for surveillance techniques, treatment options, and management of long-term consequences.

Molecular and genomic characterisation of a panel of human anal cancer cell lines.

Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue.

Regulatory T Cells Shape the Differential Impact of Radiation Dose-Fractionation Schedules on Host Innate and Adaptive Antitumor Immune Defenses.

Purpose: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT).

Methods And Materials: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or -depleting agents. Tumor growth was monitored as a readout of therapeutic response.

CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory.

Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma.

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration.

Abscopal Regressions of Lymphoma After Involved-Site Radiation Therapy Confirmed by Positron Emission Tomography.

Purpose: Patients with abscopal regressions of lymphoma after palliative involved-site radiation therapy (ISRT), detected on sequential F-fluorodeoxyglucose positron emission tomography (FDG-PET), were identified by audit. A retrospective analysis was subsequently conducted to estimate the frequency of abscopal regression in follicular lymphoma (FL).

Methods And Materials: Potential cases were identified at multidisciplinary lymphoma meetings and fulfilled these criteria: (1) palliative ISRT given for histologically confirmed lymphoma, (2) >2 lesions visualized on FDG-PET, (3) >1 unirradiated lesion(s) outside ISRT volume, (4) no systemic therapy delivered <2 months before radiation therapy or between radiation therapy and response assessment, (5) complete metabolic response (CMR) in ≥1 unirradiated lesions detected on serial FDG-PET/CT.

A novel immunogenic mouse model of melanoma for the preclinical assessment of combination targeted and immune-based therapy.

Both targeted therapy and immunotherapy have been used successfully to treat melanoma, but the development of resistance and poor response rates to the individual therapies has limited their success. Designing rational combinations of targeted therapy and immunotherapy may overcome these obstacles, but requires assessment in preclinical models with the capacity to respond to both therapeutic classes. Herein, we describe the development and characterization of a novel, immunogenic variant of the BrafCdkn2aPten YUMM1.

A Functional Immune System Is Required for the Systemic Genotoxic Effects of Localized Irradiation.

Purpose: Nontargeted effects of ionizing radiation, by which unirradiated cells and tissues are also damaged, are a relatively new paradigm in radiobiology. We recently reported radiation-induced abscopal effects (RIAEs) in normal tissues; namely, DNA damage, apoptosis, and activation of the local and systemic immune responses in C57BL6/J mice after irradiation of a small region of the body. High-dose-rate, synchrotron-generated broad beam or multiplanar x-ray microbeam radiation therapy was used with various field sizes and doses.

Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4Foxp3 Cell-Mediated Modulation of CD103 Dendritic Cells.

Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy.

Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors.

Background: Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients.

Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses.

The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam.

HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2 Tumors.

Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2 tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells.

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells.

Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses.

Lethal giant larvae-1 deficiency enhances the CD8(+) effector T-cell response to antigen challenge in vivo.

Lethal giant larvae-1 (Lgl-1) is an evolutionary conserved protein that regulates cell polarity in diverse lineages; however, the role of Lgl-1 in the polarity and function of immune cells remains to be elucidated. To assess the role of Lgl-1 in T cells, we generated chimeric mice with a hematopoietic system deficient for Lgl-1. Lgl-1 deficiency did not impair the activation or function of peripheral CD8(+) T cells in response to antigen presentation in vitro, but did skew effector and memory T-cell differentiation.

Building immunity to cancer with radiation therapy.

Over the last decade there has been a dramatic shift in the focus of cancer research toward understanding how the body's immune defenses can be harnessed to promote the effectiveness of cytotoxic anti-cancer therapies. The ability of ionizing radiation to elicit anti-cancer immune responses capable of controlling tumor growth has led to the emergence of promising combination-based radio-immunotherapeutic strategies for the treatment of cancer. Herein we review the immunoadjuvant properties of localized radiation therapy and discuss how technological advances in radio-oncology and developments in the field of tumor-immunotherapy have started to revolutionize the therapeutic application of radiotherapy.

The curative outcome of radioimmunotherapy in a mouse breast cancer model relies on mTOR signaling.

Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137] and blocking coinhibition [α-PD-1] [corrected], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative.