Faculty Bibliography

Hormone receptor (HR)⁺ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR⁺ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR⁺HER2^- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR⁺ BC.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

The ability of focal radiotherapy to promote priming of tumor-specific CD8+ T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of CTLA-4-blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

For over a century, ionising radiation has been used to treat cancer based on its cytotoxic effects on tumour cells. Technical progress has enabled more precise targeting of the tumour to reduce normal tissue toxicity while delivering higher radiation doses per fraction of treatment.In 1953, unexpected regression in lesions outside of the irradiated field were noted by an observant physician, RH Mole, who named such phenomenon "abscopal effect" from the Latin ab (position away from) and scopus (mark or target), in an article published in this journal. Clinical abscopal responses have been reported over the years but because of their very rare occurrence they could not be methodically studied, remaining akin to a curiosity. Nevertheless, their occurrence has ignited interest in studying the systemic effects of radiotherapy. Progress in dissecting the mechanisms that govern the function of the immune system in cancer has enabled to study the implication of immunity in the abscopal effect of radiation. It has become clear that ionising radiation activates canonical pathways of response to viral infections, and can stimulate antitumour immunity. These immune stimulatory effects of radiation have become clinically relevant in the current era of cancer immunotherapy, rendering abscopal responses in patients an attainable aim. Here, we will briefly review the parallel evolutions of two separate fields of medicine, radiation therapy and cancer immunology, and discuss their therapeutic partnership.

Programmed cell death protein 1 (PD-1) blockade is only effective in a minority of patients, prompting the search for combinatorial therapies that increase responses. Identifying effective combinations requires lengthy testing and so far has shown few successes. To accelerate progress Voorwerk and colleagues (Nat Med. 25(6):920-8, 2019) used an adaptive trial design to compare 4 short-course therapies (radiotherapy, cyclophosphamide, cisplatin and doxorubicin) for their ability to improve the tumor immune microenvironment and enhance responses to subsequent PD-1 blockade in women with metastatic triple negative breast cancer, a disease with low response rate to PD-1 blockade. They reported the first phase of the trial that enrolled 12 to 17 patients per arm to "pick the winner" induction treatment. Higher objective response rates (ORR) compared to no induction were observed only in the arm containing doxorubicin, which proceeded to phase II. These results raise a number of questions about testing local versus systemic induction treatments and whether sequencing with PD-1 blockade is appropriate in light of evidence supporting concomitant treatment, at least for radiotherapy. Small imbalances in baseline characteristics can also influence results obtained with limited numbers of patients per arm. We hope that these considerations will help future adaptive, signal-finding combination immunotherapy studies.

Stereotactic radiosurgery is a safe and effective technology that can address a variety of neurosurgical conditions, but in many parts of the world, access remains an issue. Although the technology is increasingly available in the United States, Canada, Europe, and parts of Asia, poor access to central nervous system (CNS) imaging and inadequate treatment equipment in other parts of the world limit the availability of radiosurgery as a treatment option. In addition, epidemiologic data about cancer and CNS metastases in low-income countries are sparse and much less complete than in more developed countries, and the need for radiosurgery may be underestimated as a result. Current radiosurgical platforms can be expensive to install and require a substantial amount of personnel training for safe operation. Socioeconomic and political forces are relevant to limitations to and opportunities for improving access to care. Here we examine the current barriers to access and propose areas for future efforts to improve global availability of radiosurgery for neurosurgical conditions.