Faculty Bibliography

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.

PURPOSE/OBJECTIVE:Understanding the pathways and gateways to leadership and challenges faced by individuals in such roles can inform efforts to promote diversity and equity. We sought to describe the professional experiences and personal characteristics of academic radiation oncology (RO) chairs and to evaluate whether differences exist by gender. METHODS AND MATERIALS/METHODS:tests, rank-sum, and t tests (significance P < .05). RESULTS:A total of 72 chairs responded (61 male, 10 female, 1 declined to identify gender) for a response rate of 76%. There were no significant gender differences in age, academic rank, publications, or prior leadership positions held at the time of the first chair appointment, but female respondents held significantly greater total direct funding from extramural grants than their male counterparts (median, $1.89 million [interquartile range, $0.5-$5 million] vs $0.25 million [interquartile range, $0-$1.0 million]; P = .006). Women were more likely to have spouses employed outside the home at time of their first chair appointment than men were, with a trend toward women experiencing greater difficulty relocating. Men and women identified budgeting and resource allocation as their greatest professional challenges. There were no gender differences in the Leadership Practices Inventory-identified leadership domains or professional goals. CONCLUSIONS:Female RO chairs are as equally qualified as men in terms of productivity or leadership skills, but they face distinct challenges in the context of a gender-structured society. The observation of higher grant funding among women at the time of chair appointment suggests a possible need for interventions such as unconscious bias training to ensure that selection processes do not unnecessarily hold women to a higher standard.

BACKGROUND:We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). METHODS:The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. RESULTS:T cells from HD. CONCLUSIONS:Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy. TRIAL REGISTRATION/BACKGROUND:NCT01401062 .

Purpose: The aim of this review is to highlight key evidence supporting the effect of radiation therapy on tumor immunity. Conclusions: Recent findings in both the preclinical and clinical settings have provided convincing evidence of the ability of radiation therapy to influence tumor-directed immune responses, and have offered critical insights into the underlying mechanisms. Not only does radiation therapy convert the tumor microenvironment to promote robust tumor immunity, but it also enhances the generation of neoantigens and neoepitopes. Radiation therapy also shapes the TCR repertoire of CD8⁺ T cells in conjunction with immune checkpoint blockade. In conclusion, a high priority should be placed on developing rational strategies to integrate radiation therapy with immunotherapy in the clinical setting, with an emphasis on careful patient selection and identifying important correlative endpoints.

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-associated neoantigens drive ICB responses in tumors with high mutational burden. In most patients, only a few of the mutations in the cancer exome that are predicted to be immunogenic are recognized by T cells. One factor that limits this recognition is the level of expression of the mutated gene product in cancer cells. Substantial preclinical data show that radiation can convert the irradiated tumor into a site for priming of tumor-specific T cells, that is, an in situ vaccine, and can induce responses in otherwise ICB-resistant tumors. Critical for radiation-elicited T-cell activation is the induction of viral mimicry, which is mediated by the accumulation of cytosolic DNA in the irradiated cells, with consequent activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) genes (STING) pathway and downstream production of type I IFN and other pro-inflammatory cytokines. Recent data suggest that radiation can also enhance cancer cell antigenicity by upregulating the expression of a large number of genes that are involved in the response to DNA damage and cellular stress, thus potentially exposing immunogenic mutations to the immune system. Here, we discuss how the principles of antigen presentation favor the presentation of peptides that are derived from newly synthesized proteins in irradiated cells. These concepts support a model that incorporates the presence of immunogenic mutations in genes that are upregulated by radiation to predict which patients might benefit from treatment with combinations of radiotherapy and ICB.