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CD8+ and FoxP3C T-cells, may be associated with a better prognosis in colorectal cancer. We sought to investigate modulation of the immune response by preoperative radiotherapy (preopRT) and its impact on survival in locally advanced rectal cancer (LARC). Materials & Methods: We analyzed data for 237 patients with LARC who received RT. Density of TILS (CD8+ and FoxP3C) in intraepithelial (iTILs) and stromal compartments (sTILs) were evaluated from surgery pathological specimens and biopsies performed at baseline. The primary endpoint was to assess the impact of infiltration of the tumor or tumor site after preopRT on progression-free survival (PFS) and overall survival (OS). Secondary endpoints were the impact of dose fractionation scheme on TILs. Results: In univariate analysis, several factors significantly correlated (p<0.05) with PFS and/or OS (T-stage, M-stage, the delay between RT and surgery). A high level of post-treatment FoxP3C TIL density correlated significantly with a better PFS (p D 0.007). In multivariate analysis, a decrease in the CD8+/FoxP3C iTILs ratio after preopRT correlated with better PFS and OS (p D 0.049 and p D 0.024, respectively). More particularly, patients with a delta CD8+/FoxP3C <-3.8 had better PFS and OS. Interestingly, the dose fractionation scheme significantly influenced the CD8+/FoxP3+ ratio after treatment (p D 0.027) with a lower ratio with hypofractionated RT (⪢2 Gy). Conclusion: Patients with LARC who had a significant decrease in the CD8+/FoxP3C ratio after preopRT were more likely to live longer. This ratio needs to be validated prospectively to guide physicians in adjuvant treatment decision-making. [ABSTRACT FROM AUTHOR]

Background: To investigate whether patients treated for a localized prostate cancer (PCa) require a radical prostatectomy followed by postoperative radiotherapy or exclusive radiotherapy, in the modern era of image guided IMRT. Methods: 178 patients with PCa were referred for daily exclusive image guided IMRT (IG-IMRT) using an on-line 3D ultra-sound based system and 69 patients were referred for postoperative IMRT without image guidance after radical prostatectomy (RP + IMRT). Patients were matched in a 1:1 ratio according to their baseline risk group before any treatment. Late toxicity was scored using the CTV v3.0 scale. Biochemical failure was defined as a postoperative PSA ≤ 0.1 ng/mL followed by 1 consecutive rising PSA for the postoperative group of patients and by the Phoenix definition (nadir + 2 ng/mL) for the group of patients treated with exclusive radiotherapy. Results: A total of 98 patients were matched (49:49). From the start of any treatment, the median follow-up was 56.6 months (CI 95% = [49.6-61.2], range [18.2-115.1]). No patient had late gastrointestinal grade ≥ 2 toxicity in the IG-IMRT group vs. 4% in the RP + IMRT group. Forty two percent of the patients in both groups had late grade ≥ 2 genitourinary toxicity. The 5-year FFF rates in the IG-IMRT group and in the RP + IMRT groups were 93.1% [80.0-97.8] and 76.5% [58.3-87.5], respectively (p = 0.031). Conclusions: Patients with a localized PCa treated with IG-IMRT had better oncological outcome than patients treated with RP + IMRT. Further improvements in postoperative IMRT using image guidance and dose escalation are urgently needed. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy (RT) exerts its anti-tumour efficacy by inducing direct damage to cancer cells but also through modification of the tumour microenvironment (TME) by inducing immunogenic antitumor response. Conversely, RT also promotes an immunosuppressive TME notably through the recruitment of regulatory T cells (Tregs). Glycoprotein A repetitions predominant (GARP), a transmembrane protein highly expressed by activated Tregs, plays a key role in the activation of TGF-β and thus promotes the immunosuppressive action of Tregs. The development of a theranostic approach targeting GARP combining imaging and targeted radionuclide therapy (TRT) was carried out., Methods: A preclinical model of 4T1 triple negative breast tumour-bearing BALB/c mice was used to show that GARP expression is increased after external beam radiation in the TME of our cancer model. We generated a theranostic probe through the bioconjugation of the chelating agent DOTAGA onto an anti-GARP monoclonal antibody. The bioconjugation with DOTAGA allows the radiolabelling of the DOTAGA-GARP conjugate with both Indium-111 for SPECT imaging and Lutetium-177 for TRT purposes., Results: We demonstrate that GARP expression is increased following RT in vivo and can be specifically detected and quantified using in vivo SPECT imaging with [ 111 In]In-DOTAGA-GARP. In addition, 177 Lu-DOTAGA-GARP limits tumour growth in our cancer model., Conclusion: This theranostic strategy may allow for the personalization of cancer treatments by early detection of activated Tregs infiltration following RT and identification of patients likely to respond to Tregs-targeted therapy via TRT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Nanoparticle (NP) surface functionalization with proteins, including monoclonal antibodies (mAbs), mAb fragments, and various peptides, has emerged as a promising strategy to enhance tumor targeting specificity and immune cell interaction. However, these methods often rely on complex chemistry and suffer from batch-dependent outcomes, primarily due to limited control over the protein orientation and quantity on NP surfaces. To address these challenges, a novel approach based on the supramolecular assembly of two peptides is presented to create a heterotetramer displaying V H Hs on NP surfaces. This approach effectively targets both tumor-associated antigens (TAAs) and immune cell-associated antigens. In vitro experiments showcase its versatility, as various NP types are biofunctionalized, including liposomes, PLGA NPs, and ultrasmall silica-based NPs, and the V H Hs targeting of known TAAs (HER2 for breast cancer, CD38 for multiple myeloma), and an immune cell antigen (NKG2D for natural killer (NK) cells) is evaluated. In in vivo studies using a HER2+ breast cancer mouse model, the approach demonstrates enhanced tumor uptake, retention, and penetration compared to the behavior of nontargeted analogs, affirming its potential for diverse applications., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

The radiation-induced immune response is increasingly well documented. However, some aspects remain unclear, notably the role of Natural Killer (NK) cells, a subgroup of innate lymphoid cells involved in the antitumor response, in the response to RT. It therefore seems necessary to better characterize NK cells infiltrating irradiated tumors in order to better understand the mechanisms of action of RT, enabling its subsequent optimization and combination with other immunomodulatory treatments. A key technology for studying intratumoral immune cells is flow cytometry, which can simultaneously quantify and analyze the phenotype of numerous cells. Here, we propose a method for phenotyping intratumoral NK cells through flow cytometry in mice bearing colorectal tumors treated with radiotherapy. This procedure can also be used to study the radiation-induced NK cell response in a wide range of solid tumors., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: We have previously demonstrated in a murine colorectal cancer model that normofractionated RT (normoRT: 18 × 2 Gy) induced MDSC infiltration and PD-L1 expression, while hypofractionated RT (hypoRT: 3 × 8 Gy) induced Treg. Here, we wanted to assess whether the association of normoRT with treatments that target two radiation-induced immunosuppressive pathways (MDSC and PD-L1) could improve tumor control., Materials and Methods: Subcutaneous tumors were induced using colon tumor cells (CT26) in immunocompetent mice (BALB/c) and were treated with RT alone (18 × 2 Gy or 3 × 8 Gy), or concomitantly with 5-Fluorouracil (5FU) (10 mg/kg) to deplete MDSC, and/or anti-PD-L1 (10 mg/kg). We assessed the impact of these combinations on tumor growth and immune cells infiltration by flow cytometry. In addition, we performed tumor rechallenge experiments and IFN-γ ELISpots to study the long-term memory response., Results: Even though tumor growth was significantly delayed in the RT + 5FU compared to 5FU and untreated groups ( p < .05), there was no significant difference between RT + 5FU (CRT) and RT alone. The rate of MDSC increased significantly 1 week after the end of normoRT (8.09% ± 1.03%, p < .05) and decreased with the addition of 5FU (3.39% ± 0.69%, p < .05). PD-L1 expressing tumor cells were increased after treatment. Adding anti-PD-L1 significantly delayed tumor growth, achieved the highest complete response rate, and induced a long-lasting protective specific anti-tumor immunity., Conclusions: These results tend to demonstrate the interest of inhibiting two radiation-induced immunosuppressive mechanisms. In patients, the combination of normoRT with 5FU is already the standard of care in locally advanced rectal cancer. Adding an anti-PD-L1 to this treatment could show promising results.