Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors

Darragh, Laurel B.; Gadwa, Jacob; Pham, Tiffany; Court, Benjamin Van; Neupert, Brooke; Olimpo, Nicholas A.; Nguyen, Khoa; Nguyen, Diemmy; Knitz, Michael; Hoen, Maureen; Corbo, Sophia; Joshi, Molishree; Zhuang, Yonghua; Amann, Maria; Wang, Xiao‐Jing; Dow, Steven; Kedl, Ross M.; Samedi, Von; Boss, Mary‐Keara; Karam, Sana D.

doi:10.1038/s41467-022-34676-w

Cited by 97 publications

(51 citation statements)

References 63 publications

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“…However, there is concern that the tumor draining lymph nodes should be spared from radiation therapy, as these are the sites of immune cell activation and expansion. [ 57,58 ] Consistent with this, our results suggest that nodal irradiation can be counter‐productive in patients with tumors that have low antigen production, because of toxic effects on proliferating T cells in the active nodes. This effect is less prominent when tumor antigen production is high because nT‐cell activation is more frequent, and not rate‐limiting.…”

Section: Discussionsupporting

confidence: 85%

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

Nikmaneshi,

Baish,

Zhou

et al. 2023

Advanced Science

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Effective anti‐cancer immune responses require activation of one or more naïve T cells. If the correct naïve T cell encounters its cognate antigen presented by an antigen presenting cell, then the T cell can activate and proliferate. Here, mathematical modeling is used to explore the possibility that immune activation in lymph nodes is a rate‐limiting step in anti‐cancer immunity and can affect response rates to immune checkpoint therapy. The model provides a mechanistic framework for optimizing cancer immunotherapy and developing testable solutions to unleash anti‐tumor immune responses for more patients with cancer. The results show that antigen production rate and trafficking of naïve T cells into the lymph nodes are key parameters and that treatments designed to enhance tumor antigen production can improve immune checkpoint therapies. The model underscores the potential of radiation therapy in augmenting tumor immunogenicity and neoantigen production for improved ICB therapy, while emphasizing the need for careful consideration in cases where antigen levels are already sufficient to avoid compromising the immune response.

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Section: Discussionsupporting

confidence: 85%

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

Nikmaneshi,

Baish,

Zhou

et al. 2023

Advanced Science

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“…Recently two different head and neck studies highlight that lymphatic preserving treatments favor systemic antitumor immunity, whereas elective nodal irradiation may decrease immune cell functionality. 41 , 42 One may argue that this was the case of conventionally fractionated RT (Group-3) where both prostatic bed and pelvic lymph nodes were irradiated. Sini et al 43 has shown how whole pelvis RT in PCa can induce hematological toxicity, and the use of specific constraints on bone marrow may help limiting this effect.…”

Section: Discussionmentioning

confidence: 99%

Stereotactic Ablative Radiation Therapy in 3 Fractions Induces a Favorable Systemic Immune Cell Profiling in Prostate Cancer Patients

Palermo¹,

Bottero

Panetta³

et al. 2023

OncoImmunology

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The impact of radiotherapy (RT) on immune cell status in prostate cancer (PCa) is only partially determined. The aim of this study was to assess the effect of different RT strategies on peripheral B, T, and Natural killer (NK) lymphocytes at precise longitudinal time-points in PCa. 18 patients treated with stereotactic body radiation therapy (SBRT) (40 Gy/3FRX), definitive moderate-hypofractionation (62 Gy/20FRX), or post-operative conventional-fractionation RT (66–69 Gy/30FRX) were prospectively evaluated for the immune cell profile in terms of immune cell composition, differentiation stage, cytokine production and inhibitory receptor (IR) expression. The immune-monitoring of the 18 patients revealed that RT affects the balance of systemic immune cells, with the main differences observed between SBRT and conventionally fractionated RT. SBRT favorably impacts immune response in term of increased B cells, central-memory and effector-memory CD8 + T cells, along with decreased Treg cells after treatment. On the contrary, conventional fractionated RT had a long-term negative effect on the systemic immune profile, including a decrease of total lymphocyte counts accompanied by an increase of neutrophils-to-lymphocytes ratio. Total B and T cells decreased and Treg-to-CD8 + ratio increased. Functionality of T lymphocytes were not affected by any of the 3-fractionation schedules. Interestingly, SBRT significantly up-regulates the expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) in CD8 + T cells in the absence of other IRs. Our results indicate the relevance of systematic immunomonitoring during RT to identify novel immune-related target to design trials of combined radio-immunotherapy as a promising strategy in the clinical management of PCa.

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“…However, once immune memory is established, anti‐tumour immunity ceases to rely on TDLNs. Radiation therapy solely targeting the primary tumour can enhance the effectiveness of immunotherapy, while selective radiation targeting the lymph nodes can mitgate this effect 95 . Saddawi et al.…”

Section: Dilemmas and Prospectsmentioning

confidence: 99%

“…Radiation therapy solely targeting the primary tumour can enhance the effectiveness of immunotherapy, while selective radiation targeting the lymph nodes can mitgate this effect. 95 Saddawi et al conducted an additional preclinical study probing the role of TDLNs in immune checkpoint inhibitor (ICI) therapy. Employing a murine model in this experiment, they observed that the surgical removal of lymph nodes prior to ICI therapy significantly decreased overall survival rates.…”

Section: The Role Of Tdlns In Immunotherapy For Osccmentioning

confidence: 99%

Lymph node metastasis in oral squamous cell carcinoma: Where we are and where we are going

Cao

Zhong

et al. 2023

Clinical and Translational Dis

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BackgroundOral cancer is a common malignant tumour in the head and neck region, with over 90% of cases being oral squamous cell carcinoma (OSCC). Lymph node metastasis (LNM) is a significant adverse prognostic factor in OSCC; however, the mechanism of LNM in OSCC remains unclear, while the strategies for managing cervical lymph nodes (CLNs) in OSCC continue to evolve. At present, neck dissection is necessary for the vast majority of OSCC patients, but complications of surgery can significantly impair patients’ postoperative quality of life. A recent clinical trial discovery indicates that immunotherapy can activate anti‐tumour T cells in nearby lymph nodes, leading to vibrant discussions among clinicians about the importance of preserving lymph nodes during surgical treatment.AimThis review aims to provide an overview of where we are: the current knowledge of OSCC LNM patterns and management strategies, and where we are going: prospects for clinical and basic research on the issue of OSCC LNM in the era of cancer immunotherapy.ResultWe summarize the general patterns and management strategies of OSCC LNM. The process of LNM in OSCC encompasses four stages: Preparation, Unleash, Migration, and Planting (‘PUMP’ principle). We propose adopting the ‘PRECISE’ model, an overall workflow that includes seven elements—prevention, radiology, preoperative evaluation, chemotherapy, immunotherapy, surgery, and postoperative evaluation—for neck management in OSCC, promoting personalized precision medicine augmented by neoadjuvant therapy. We further discussed recent advances in clinical and basic research on OSCC LNM and provided an outlook on future research directions.ConclusionOver the past two centuries, our understanding and management strategies of LNM in OSCC have evolved, seeking more precise and personalized approaches to reduce patient burden and enhance survival and quality of life. Further research should explore lymph nodes’ role in cancer immunotherapy and OSCC interactions, leading to better, less invasive treatments and improved outcomes.

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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors

Cited by 97 publications

References 63 publications

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

Transport Barriers Influence the Activation of Anti‐Tumor Immunity: A Systems Biology Analysis

Stereotactic Ablative Radiation Therapy in 3 Fractions Induces a Favorable Systemic Immune Cell Profiling in Prostate Cancer Patients

Lymph node metastasis in oral squamous cell carcinoma: Where we are and where we are going

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