Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

Deng, Lu; Liang, Hua; Burnette, Byron; Beckett, Michael A.; Darga, Thomas E.; Weichselbaum, Ralph R.; Fu, Yang Xin

doi:10.1172/jci67313

Cited by 1,662 publications

(1,428 citation statements)

References 43 publications

(57 reference statements)

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“…Whereas anti-Ly6G antibody-mediated neutrophil depletion improves the efficacy of radiotherapy in a subcutaneous colon cancer model 193 , antibody-mediated depletion of Gr1 + cells does not alter radiotherapy responses of xenografted prostate cancer cells 194 .…”

Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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“…89 Combining PD-1/PD-L1 inhibitors and radiotherapy: (1) reduced the number of MDSCs in the tumor microenvironment; (2) increased CD8 þ to T reg ratio; and (3) enhanced CD8 þ infiltration and thus, augmented the antitumor response. [90][91][92] Moreover, substantial data have proposed a positive role of combining PD-1/PD-L1 inhibitors and radiotherapy in different types of tumors, 92,93 including NSCLC. 91 Therefore, with the perspective of the preclinical data, several studies tried to translate this promising modality into clinical practice in the treatment of NSCLC (NCT02400814, NCT02463994, and NCT02407171; Table 1).…”

Section: Combined With Radiotherapymentioning

confidence: 99%

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

Marinis

Ardizzoni

Fontanini

et al. 2014

Clinical Lung Cancer

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“…Conversely, the depletion of neutrophilic MDSCs potentiates the efficacy of radiotherapy on subcutaneous colon cancer cells [97], presumably through the alleviation of T cell suppression. Dendritic cells also play a role in radiosensitivity [58,96,98], but their activation by irradiation varies between transplantable models.…”

Section: Innate Immune Cellsmentioning

confidence: 99%

“…By contrast, the synergy between cisplatin, a chemotherapeutic that does not affect immunosuppressive cells, and anti-CTLA4 is controversial [170,173]. Radiotherapy also synergizes with CTLA4, PDL1 and combined CD40/CD137 targeting to control the growth of various transplantable models and lung metastases [97,174,175] -a process that is dependent on CD4 + T cells, CD8 + T cells, NK cells or all of the above [97,174]. These data suggest that intervention strategies that induce a favorable T cell influx and/or reduced Foxp3/CD8 ratio in tumors are efficacious partners for checkpoint inhibitors.…”

Section: Immunotherapeutic Strategies To Enhance the Response To Antimentioning

confidence: 99%

“…Similar results are observed using other strategies to block TAMs, including CSF1R inhibitors in combination with fractionated irradiation in subcutaneous prostate tumors [91] and carrageenan in transplantable models [92]. In B16 melanomas, however, the anti-cancer effect of a single local high radiotherapy dose is not affected by the absence of TAMs [96].Depletion of Ly6G + neutrophils and Ly6C + inflammatory monocytes using Gr1 antibodies has no synergistic effect with radiotherapy in subcutaneous human prostate tumors [89].Conversely, the depletion of neutrophilic MDSCs potentiates the efficacy of radiotherapy on subcutaneous colon cancer cells [97], presumably through the alleviation of T cell suppression. Dendritic cells also play a role in radiosensitivity [58,96,98], but their activation by irradiation varies between transplantable models.…”

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Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

121

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

Abstract: High-dose ionizing irradiation (IR) results in direct tumor

Cited by 1,662 publications

References 43 publications

Neutrophils in cancer: neutral no more

Neutrophils in cancer: neutral no more

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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