High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade.

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response.

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

Actitudes de las personas usuarias de atención primaria ante el cribado del cáncer colorrectal / Attitudes of primary health care users to a colorectal cancer screening program

Objetivo: Conocer las condiciones sociales, culturales y de género que determinan las actitudes de las personas de 50 a 69 años de edad usuarias de atención primaria de salud ante el cribado poblacional del cáncer colorrectal. Método: Diseño etnográfico con perspectiva de género. Las técnicas utilizadas fueron grupos de discusión y diario de campo. Los participantes eran hombres y mujeres de entre 50 y 69 años de edad, en Baleares y Barcelona. Resultados: El elemento clave es el diagnóstico a tiempo. Mientras que antes se consideraba el cáncer como una enfermedad incurable, actualmente se concibe como un problema serio que puede curarse si se diagnostica a tiempo. Se percibe un sentimiento de preocupación por la salud, en especial en los hombres. Los participantes demandan más información sobre el cáncer y se sienten vulnerables a padecerlo, principalmente por la edad. Ante los síntomas, los hombres consideran importante escucharlos, pero para las mujeres es mejor obviarlos. Se observa una actitud positiva ante el cribado del cáncer colorrectal, incluso ante la colonoscopia, aunque en las mujeres se perciben algunas barreras como el miedo a tener cáncer. Conclusiones: La oportunidad de un diagnóstico precoz es el elemento clave para promover la participación en un programa de cribado del cáncer colorrectal. Las diferentes percepciones de hombres y mujeres modulan su predisposición a participar. En concreto, la preocupación por la salud de los hombres y en especial el temor de las mujeres a que se les diagnostique un cáncer son factores a tener en cuenta (AU)

Objective: To describe the cultural, social and gender features that determine attitudes to colorectal cancer screening in a target group of patients aged 50 to 69 years old in the primary health care setting. Methods: We performed a qualitative ethnographic study from a gender perspective. Participants consisted of men and women aged 50 to 69 years old in the Balearic Islands and Barcelona. Group discussion and a field diary were used. Results: The key element was diagnosis at an early stage. Until recently, cancer was considered an incurable disease but is currently perceived as a serious health problem that can be cured if diagnosed promptly. The participants requested more information on cancer and felt they were at risk, mainly because of their age. Men tended to pay attention to symptoms while women tended to ignore them. Attitudes to colorectal cancer screening were generally positive, even to colonoscopy. Some barriers to screening were identified in women, such as a fear of having cancer. Conclusions: The opportunity for early diagnosis is the key element in promoting participation in a colorectal cancer screening program. Perceptions-and hence willingness to participate in screening-differ between men and women. Factors to be taken into account in the design of population-based colorectal cancer programs are health concerns in men and fear of a cancer diagnosis in women (AU)

[Attitudes of primary health care users to a colorectal cancer screening program]. / Actitudes de las personas usuarias de atención primaria ante el cribado del cáncer colorrectal.

OBJECTIVE: To describe the cultural, social and gender features that determine attitudes to colorectal cancer screening in a target group of patients aged 50 to 69 years old in the primary health care setting. METHODS: We performed a qualitative ethnographic study from a gender perspective. Participants consisted of men and women aged 50 to 69 years old in the Balearic Islands and Barcelona. Group discussion and a field diary were used. RESULTS: The key element was diagnosis at an early stage. Until recently, cancer was considered an incurable disease but is currently perceived as a serious health problem that can be cured if diagnosed promptly. The participants requested more information on cancer and felt they were at risk, mainly because of their age. Men tended to pay attention to symptoms while women tended to ignore them. Attitudes to colorectal cancer screening were generally positive, even to colonoscopy. Some barriers to screening were identified in women, such as a fear of having cancer. CONCLUSIONS: The opportunity for early diagnosis is the key element in promoting participation in a colorectal cancer screening program. Perceptions-and hence willingness to participate in screening-differ between men and women. Factors to be taken into account in the design of population-based colorectal cancer programs are health concerns in men and fear of a cancer diagnosis in women.

A cross-sectional study of the appropriateness of colonoscopy requests in the Spanish region of Catalonia.

INTRODUCTION: Colonoscopies are being requested with increasing frequency in the last few years, as they are used both as a diagnostic and therapeutic procedure in several gastrointestinal diseases. Our purpose is to describe the appropriateness of colonoscopy requests issued both from primary care centres and from hospitals, according to the EPAGE II guidelines (European Panel on the Appropriateness of Gastrointestinal Endoscopy). METHODS AND ANALYSIS: Cross-sectional study. Colonoscopy requests issued since January 2011 and received at the endoscopy units of all six reference hospitals serving the primary care centres of the South Metropolitan and Central Catalonia districts will be collected (total=1500 requests). Variables to be collected include gender, date of birth, origin of the request and reference hospital, priority of the procedure, type of clinician requesting the procedure, date and indication of request, abdominal examination performed, anal inspection examination performed, date of last colonoscopy if applicable, diagnosis and date of diagnosis. Using the available information and the EPAGE II website, colonoscopy requests will be assigned as an appropriateness score. The association between the variables collected and the EPAGE II scores will be assessed using a Student's t test and a χ(2) test. A multilevel logistic model will be generated on the factors associated with the appropriateness of the requests. ETHICS AND DISSEMINATION: Colonoscopy is a costly procedure and not free from complications. In order to increase cost effectiveness, reduce waiting lists and optimise resources, it is necessary to use tools such as the EPAGE II guidelines, which establish criteria to assess the appropriateness of colonoscopies. The purpose of this study is to describe the current situation and to discuss whether current clinical practice is appropriate. The results of the study will be published in the next few years. In consideration of the ethical principles and methods of the research study, approval was granted for the project.