Radiation response and combination target discovery in a novel model of rectal cancer

Rectal cancer is typically treated with radiotherapy, with or without chemotherapy, prior to surgical resection of the tumour. However, in patients that respond poorly to radiation, tumours largely lack significant immune cells within the surrounding milieu and present with a CAF-rich stroma. We have recapitulated this radioresistant phenotype in vivo through the implantation of Apcfl/fl, KrasG12D/+, Trp53fl/fl, TgfbrIfl/fl (AKPT) organoids. Here, through the irradiation of the heterotopic AKPT model, we have identified two targets for inhibition to augment the anti-tumour effect of radiation: complement C5a receptor 1 (C5aR1) and transforming growth factor beta (TGF-β). We demonstrated that inhibiting C5aR1 increased the effectiveness of irradiation in the AKPT model both in vitro and in vivo. Inhibiting C5aR1 in vitro had a direct impact on tumour cell radiosensitivity in the AKPT organoid model. In vivo we demonstrated that bolstering radiation through C5aR1 inhibition acts independently to the T-cell population, as shown in athymic mice bearing AKPT tumours heterotopically. Furthermore, we hypothesise that additional effects on the macrophage and cancer-associated fibroblast (CAF) populations could contribute to the augmentation of radiation anti-tumour effects when C5aR1 is inhibited. We demonstrate an increase in the inflammatory macrophage population, as well as a shift in the CAF phenotype. Interestingly, the modest radiosensitisation observed in vitro suggest that¸ in the in vivo AKPT model, mechanisms altering the macrophage and CAF populations may be of greater importance than increased intrinsic radiosensitivity. We also demonstrate that the inhibition of TGF-β increased the effectiveness of radiation in vivo in the AKPT heterotopic model. Furthermore, we show that the inhibition of this multifunctional cytokine, when combined with irradiation, has a dramatic effect on both the immune cells and CAFs within the tumour milieu. These changes include a significant increase of cytotoxic T-cell infiltration of the tumour epithelium, a significant decrease in the Treg population, a shift in the macrophages toward a more inflammatory phenotype, and a shift in the CAF phenotype. These changes were reflected by the enrichment of immunogenic gene signatures in the AKPT model after treatment with radiation combined with TGF-β inhibition, with immunosuppressive signatures showing a corresponding negative enrichment. We hypothesise that the shift in the CAF population phenotype is directly linked to the increase immunogenic action against the tumour. We further suggest that in the AKPT rectal cancer model, the CAF population acts to orchestrate the sustained immune response after irradiation, provided TGF-β is inhibited

The association between rurality and return to work for workers’ compensation claimants with work-related musculoskeletal injuries: An analysis of workers who failed to return to work within typical healing time frames

Objectives: The objectives of this study have been to: 1) describe and compare urban and rural injured worker populations in Alberta, Canada; 2) identify return-to-work outcomes in urban and rural populations; 3) examine the relationship between geographic location of residence and recovery from work-related musculoskeletal injury; and 4) investigate if this relationship is attenuated after controlling for other known risk factors. Material and Methods: This study was a secondary analysis utilizing data of a population of musculoskeletal injury claimants who underwent clinical/RTW (return to work) assessment between December 2009 and January 2011 collected by the Workers’ Compensation Board of Alberta. Descriptive statistics were computed for 32 variables and used for comparing urban and rural workers. The logistic regression analysis was performed to test the association between geographic location of residence and likelihood of return-to-work. Results: Data on 7843 claimants was included, 70.1% of them being urban and 29.9% – rural. Rural claimants tended to have spent less time in formal education, have a blue-collar job, have no modified work available, have a diagnosed comorbidity, and not been enrolled in a specialized rehabilitation program. They were 1.43 (1.12–1.84) times the odds more likely than urban claimants to be continuing to receive full disability benefits 90 days after their RTW assessment, and 1.68 (1.06–2.67) times the odds as likely to report a recurrence of receiving disability benefits. Conclusions: Rural residence was associated with prolonged work disability, even after controlling for age, job type, education level, health utilization and other potential confounders. Further research is required to explore why injured workers in rural settings experience prolonged reception of disability benefits and have greater rates of recurrence of receiving disability benefits. Int J Occup Med Environ Health 2017;30(5):715–72

The effects of radiation therapy on the macrophage response in cancer

The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively “reprogram” TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features