The role of dendritic cells in radiation-induced immune responses

Kaur, Aanchal Preet; Alice, Alejandro F.; Crittenden, Marka R.; Gough, Michael

doi:10.1016/bs.ircmb.2023.02.002

Cited by 6 publications

(5 citation statements)

References 270 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Radiotherapy in combination with GS-3583 was allowed in the current study with the idea that radiation would provide a pool of tumor antigens that would then be engulfed by the dendritic cells, processed, and presented as antigens to T cells, thereby initiating T-cell priming ( 41 ). However, with only 3 participants receiving stereotactic radiation and no way of monitoring T-cell receptor repertoire, we have no way of knowing if the radiation had the desired effect.…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors

Tolcher,

Brody,

Rajakumaraswamy

et al. 2024

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: GS-3583, a FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDCs) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell–mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. Patients and Methods: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. Results: Thirteen participants enrolled in 4 dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44–79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2–20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all 4 doses with a dose-dependent trend in the durability of the cDC expansion. Conclusions: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors

Tolcher,

Brody,

Rajakumaraswamy

et al. 2024

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…While these modalities were not designed as immunotherapies, the immune system is critical to their overall effectiveness. Chemotherapy and radiation therapy generate tumor immunity predominantly through induction of DC mediated immunogenic cell death (ICD) of tumor cells ( 97 , 98 ) ( Figure 3 ). After insult by cytotoxic agents, DAMPs such as calreticulin (CRT), HSP70 and HSP90, HMGB1, and ATP are released.…”

Section: Role Of Dcs In Existing Cancer Therapiesmentioning

confidence: 99%

Dendritic cell subsets and implications for cancer immunotherapy

Chen,

Zhang,

Goedegebuure

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

show abstract

“…For example, immunotherapies that target exhausted T-cells, such as checkpoint inhibitors, will likely be most successful where the patient has an extensive immune infiltrate limited by expression of these checkpoint molecules. By contrast, where a patient lacks extensive pre-existing immunity, the optimum immunotherapy may be better targeted to initiate anti-tumor immune responses in the tumor-draining lymph nodes, focusing on DC-related innate adjuvants ( 29 – 31 ), or costimulatory molecules such as ICOS and OX40 that are induced following antigen exposure ( 130 , 131 ). A range of immune interventions in combination with radiation are discussed below.…”

Section: The Immunogenic Radiationmentioning

confidence: 99%

“…Understanding the pattern of innate adjuvants released by dying cancer cells is critical, since some forms of cell death are differentially immunogenic (21)(22)(23). Similarly, the cell types that respond to these adjuvants and their differentiation dramatically impact the immune consequences of cancer cell death and adjuvant release (24)(25)(26)(27)(28)(29). Thus, if the response to radiation is optimal, cancer cell death will release antigen and adjuvant to promote dendritic cells (DC) maturation to boost existing T-cell responses and generate new T-cell responses.…”

Section: The Immunogenic Radiation and Sbrtmentioning

confidence: 99%

“…Signal 2 is an essential second step in T-cell activation provided by the antigen-presenting cell in response to adjuvant signals in their environment. Signal 2 is delivered by costimulatory molecules such as CD80 and CD86 that are induced on antigen-presenting cells following their exposure to innate adjuvants, as well as following antigen presentation to CD4 + T-cells (29,(102)(103)(104)(105). In the case of infectious disease, these immunological adjuvants are bacterial or viral components directly recognized by Toll-Like Receptor or similar pathways in the antigen-presenting cell.…”

Section: Cancer Cell Death As a Source Of Antigen And Adjuvantmentioning

confidence: 99%

See 1 more Smart Citation

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

Sharon,

Daher-Ghanem,

Zaid

et al. 2023

Front. Oral. Health

Self Cite

View full text Add to dashboard Cite

Although treatment modalities for head and neck cancer have evolved considerably over the past decades, survival rates have plateaued. The treatment options remained limited to definitive surgery, surgery followed by fractionated radiotherapy with optional chemotherapy, and a definitive combination of fractionated radiotherapy and chemotherapy. Lately, immunotherapy has been introduced as the fourth modality of treatment, mainly administered as a single checkpoint inhibitor for recurrent or metastatic disease. While other regimens and combinations of immunotherapy and targeted therapy are being tested in clinical trials, adapting the appropriate regimens to patients and predicting their outcomes have yet to reach the clinical setting. Radiotherapy is mainly regarded as a means to target cancer cells while minimizing the unwanted peripheral effect. Radiotherapy regimens and fractionation are designed to serve this purpose, while the systemic effect of radiation on the immune response is rarely considered a factor while designing treatment. To bridge this gap, this review will highlight the effect of radiotherapy on the tumor microenvironment locally, and the immune response systemically. We will review the methodology to identify potential targets for therapy in the tumor microenvironment and the scientific basis for combining targeted therapy and radiotherapy. We will describe a current experience in preclinical models to test these combinations and propose how challenges in this realm may be faced. We will review new players in targeted therapy and their utilization to drive immunogenic response against head and neck cancer. We will outline the factors contributing to head and neck cancer heterogeneity and their effect on the response to radiotherapy. We will review in-silico methods to decipher intertumoral and intratumoral heterogeneity and how these algorithms can predict treatment outcomes. We propose that (a) the sequence of surgery, radiotherapy, chemotherapy, and targeted therapy should be designed not only to annul cancer directly, but to prime the immune response. (b) Fractionation of radiotherapy and the extent of the irradiated field should facilitate systemic immunity to develop. (c) New players in targeted therapy should be evaluated in translational studies toward clinical trials. (d) Head and neck cancer treatment should be personalized according to patients and tumor-specific factors.

show abstract

The role of dendritic cells in radiation-induced immune responses

Cited by 6 publications

References 270 publications

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors

Dendritic cell subsets and implications for cancer immunotherapy

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

Contact Info

Product

Resources

About