Dataset Information

41BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine breast tumor

ABSTRACT: Background: Ionizing radiation (IR) is a double-edge sword for immunotherapy as it may cause both immunosuppressive and immunostimulatory effects. The interactions of IR with the tumor microenvironment (TME) is a key factor for this balance. Fibroblast activation protein (FAP) is expressed on the surface of CAFs in many cancer types and its presence is associated with poor immune response to immune checkpoint blockade in patients. We hypothesize that IR increases FAP expression in CAFs, therefore the combination of IR with targeted immunomodulators such as an agonistic FAP-4-1BBL bispecific antibody fusion protein could enhance the immune-mediated antitumoral effect of these treatments given in combination. Methods: Murine transplantable TS/A tumor cells line was used to investigate increases in FAP expression in tumors after irradiation by IHQ and RT-PCR. We treated bilateral tumor-bearing mice in which only one of the lesions was locally irradiated (2 × 6 Gy) given alone or in combination with a systemic administration of the FAP-4-1BBL bispecific construct. Tumor sizes were followed over time and in the cellular composition microenvironment (TME) was assessed by immunochemistry and multiplex tissue immunofluorescence. Selective depletions of immune cell populations were used to delineate the immune system requirements for efficacy. Antibody of interest was labeled and tracked its distribution by CT. Colorectal carcinoma samples were also validated. Results: Irradiation of TS/A+CAF tumors showed clear increases of FAP expression levels after local irradiation. The suboptimal radiotherapy regimen in combination with FAP targeted 4-1BBL worked to attain primary tumor control as well as partial abscopal effect. Immune landscape analysis showed an effector and proinflammatory phenotype with an increased infiltration of immune cells. The antitumoral mechanism relied on CD8+ T cells, IFN-I, IFN-γ and CD137 expression. Biodistribution studies of bispecific antibody performed indicated enhanced tumor targeting after tumor irradiation. Human sample results confirmed enhanced immune infiltration and FAP expression after radiotherapy treatment. Conclusion: Our data provides a proof- of- concept and mechanistic insights pertaining the therapeutic efficacy of bispecific FAP-41BBL combined with local radiotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE255242 | GEO | 2025/02/19

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Although it is usually described as an immunosuppressive modality and not thought of as immunotherapy, there are new preclinical evidences suggesting that high-dose ionizing irradiation (IR) results in direct tumour cell death and augments tumour-specific immunity, which enhances tumour control both locally and distantly. Importantly, IR effects exceed the classical cytocidal properties by also causing phenotypic changes in the fraction of surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination. However, not all IR-induced modifications of the tumour and its microenvironment favor immune rejection. The tumour microenvironment is populated by various types of inhibitory immune cells including Tregs, alternatively activated macrophages, and myeloid-derived suppression cells (MDSCs), which suppress T cell activation and promote tumour outgrowth. Chiang et al. showed the accumulation of pro-tumourigenic M2 macrophages in areas of hypoxia present in irradiated tumours. IR then may also induced responses that are inadequate to maintain antitumuor immunity. Close interaction between IR, T cells, and the PD-L1/PD-1 axis exsit and provide a basis for the rational design of combination therapy with immune modulators and radiotherapy. Deng et al. demonstrate that PD-L1 was upregulated in the tumour microenvironment after IR. Moreover, administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumour regression, IR and anti-PD-L1 synergistically reduced the local accumulation of tumour-infiltrating MDSCs, which suppress T cells and alter the tumour immune microenvironment. Finally, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumours through the cytotoxic actions of TNF. Sagiv-Barfi et al, also demonstrated in 5 patients receiving atezolizumab and radiation therapy, at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no serious immune-related toxicities. Abscopal out-field effects of irradiation has also been described in addition to a reduction in circulating MDSCs in a melanoma patient treated with the anti CTLA-4 ipilimumab and radiotherapy. Lastly, recent evidence demonstrates that loco-regional curative treatment with stereotactic ablative radiotherapy (SABR) is a good alternative as compared with conventional 3D RT for patients with solid tumour, with durable remissions and a low toxicity profile. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. For colorectal, non-small cell, and renal cell cancers, 1-year metastasis control rates ranged from 67 to 91%. Moreover, abscopal reponses in the setting of immune checkpoints inhibitors and radiotherapy combinations have been made in the setting of metastatic disease event in patients with extensive tumor burden. The goal of SABR is to deliver appropriate metastasis directed radiotherapy while minimizing exposure of surrounding normal tissues. Interestingly, the dose and fractionation employed modulate RT ability to synergize with immunotherapy. Vanpouille-Box et al, showed that immune response genes were differentially expressed in irradiated tumours by 8Gyx3 but not 20Gyx1. This highlight the interest of hypofractionated SABR acting as a "in situ tumour vaccine". As hypofractionated SABR may, in addition to its good local control, increase the effectiveness of anti PD-L1, investigators aimed to investigate the efficacy and the tolerability of the combination of anti-PD-L1 antibody with SABR.

Dataset Information

41BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy in murine breast tumor

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets