JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

A Review of Scheduling Strategies for Radiotherapy and Immune Checkpoint Inhibition in Locally Advanced Rectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy across the globe and, despite advances in treatment strategies, survival rates remain low. Rectal cancer (RC) accounts for most of these cases, and traditional management strategies for advanced disease include total neoadjuvant therapy (TNT) with chemoradiotherapy followed by curative surgery. Unfortunately, approximately 10-15% of patients have no response to treatment or have recurrence at a short interval following radiotherapy. The introduction of immunotherapy in the form of immune checkpoint blockade (ICB) in metastatic colorectal cancer has improved clinical outcomes, yet most patients with RC present with microsatellite stable disease, which lacks the immune-rich microenvironment where ICB is most effective. There is evidence that combining radiotherapy with ICB can unlock the mechanisms that drive resistance in patients; however, the sequencing of these therapies is still debated. This review offers a comprehensive overview of clinical trials and preclinical models that use radiotherapy-immunotherapy combinations in RC in an attempt to extrapolate the ideal sequencing of the two treatment modalities. The results highlight the dearth of evidence to answer the question of whether ICB should be given before, during, or after radiotherapy, yet it is suggested that improving the relevance of our preclinical models will provide a platform with higher translational value and will lead to appropriate clinical trial designs.

Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer.

OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.

Pre-clinical modelling of rectal cancer to develop novel radiotherapy-based treatment strategies.

Pre-operative chemoradiotherapy reduces local recurrence rates in locally advanced rectal cancer. 10-20% of patients undergo complete response to chemoradiotherapy, however, many patients show no response. The mechanisms underlying this are poorly understood; identifying molecular and immunological factors underpinning heterogeneous responses to chemoradiotherapy, will promote development of treatment strategies to improve responses and overcome resistance mechanisms. This review describes the advances made in pre-clinical modelling of colorectal cancer, including genetically engineered mouse models, transplantation models, patient derived organoids and radiotherapy platforms to study responses to chemoradiotherapy. Relevant literature was identified through the PubMed and MEDLINE databases, using the following keywords: rectal cancer; mouse models; organoids; neo-adjuvant treatment; radiotherapy; chemotherapy. By delineating the advantages and disadvantages of available models, we discuss how modelling techniques can be utilized to address current research priorities in locally advanced rectal cancer. We provide unique insight into the potential application of pre-clinical models in the development of novel neo-adjuvant treatment strategies, which will hopefully guide future clinical trials.

General job stress: a unidimensional measure and its non-linear relations with outcome variables.

This article aims to examine the non-linear relations between a general measure of job stress [Stress in General (SIG)] and two outcome variables: intentions to quit and job satisfaction. In so doing, we also re-examine the factor structure of the SIG and determine that, as a two-factor scale, it obscures non-linear relations with outcomes. Thus, in this research, we not only test for non-linear relations between stress and outcome variables but also present an updated version of the SIG scale. Using two distinct samples of working adults (sample 1, N = 589; sample 2, N = 4322), results indicate that a more parsimonious eight-item SIG has better model-data fit than the 15-item two-factor SIG and that the eight-item SIG has non-linear relations with job satisfaction and intentions to quit. Specifically, the revised SIG has an inverted curvilinear J-shaped relation with job satisfaction such that job satisfaction drops precipitously after a certain level of stress; the SIG has a J-shaped curvilinear relation with intentions to quit such that turnover intentions increase exponentially after a certain level of stress.

Developing a biodata measure and situational judgment inventory as predictors of college student performance.

This article describes the development and validation of a biographical data (biodata) measure and situational judgment inventory (SJI) as useful predictors of broadly defined college student performance outcomes. These measures provided incremental validity when considered in combination with standardized college-entrance tests (i.e., SAT/ACT) and a measure of Big Five personality constructs. Racial subgroup mean differences were much smaller on the biodata and SJI measures than on the standardized tests and college grade point average. Female students tended to outperform male students on most predictors and outcomes with the exception of the SAT/ACT. The biodata and SJI measures show promise for student development contexts and for selecting students on a wide range of outcomes with reduced adverse impact.

Impact of elaboration on socially desirable responding and the validity of biodata measures.

The current study investigated the impact of requiring respondents to elaborate on their answers to a biodata measure on mean scores, the validity of the biodata item composites, subgroup mean differences, and correlations with social desirability. Results of this study indicate that elaborated responses result in scores that are much lower than nonelaborated responses to the same items by an independent sample. Despite the lower mean score on elaborated items, it does not appear that elaboration affects the size of the correlation between social desirability and responses to biodata items or that it affects criterion-related validity or subgroup mean differences in a practically significant way.