BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment.

Approximately 50% of melanoma patients fail to respond to immune checkpoint blockade (ICB), and acquired resistance hampers long-term survival in about half of initially responding patients. Whether targeting BET reader proteins, implicated in epigenetic dysregulation, can enhance ICB response rates and durability, remains to be determined. Here we show elevated BET proteins correlate with poor survival and ICB responses in melanoma patients. The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models. Combination treatment response in the innate resistance model induced changes in tumor-infiltrating immune cells, reducing myeloid-derived suppressor cells (MDSCs). CD4+ and CD8+ T cells showed decreased expression of inhibitory receptors, with reduced TIM3, LAG3, and BTLA checkpoint expression. In human PBMCs in vitro, BET inhibition reduced expression of immune checkpoints in CD4+ and CD8+ T cells, restoring effector cytokines and downregulating the transcriptional driver TOX. BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming.

BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY: Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION: A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies.

Score based risk assessment of lung cancer and its evaluation for Bangladeshi people.

BACKGROUND: The problem of cancer, especially lung cancer, is very acute in Bangladesh. The present study was conducted to evaluate the risk of lung cancer among Bangladeshi people based on hereditary, socio-economic and demographic factors. MATERIALS AND METHODS: This study was carried out in 208 people (patients-104, controls-104) from January 2012 to September 2013 using a structured questionnaire containing details of lung cancer risk factors including smoking, secondhand smoke, tobacco leaf intake, age, gender, family history, chronic lung diseases, radiotherapy in the chest area, diet, obesity, physical activity, alcohol consumption, occupation, education, and income. Descriptive statistics and testing of hypotheses were used for the analysis using SPSS software (version 20). RESULTS: According to this study, lung cancer was more prevalent in males than females. Smoking was the highest risk factor (OR=9.707; RR=3.924; sensitivity=0.8872 and P<0.0001) followed by previous lung disease (asthma, tuberculosis etc.) (OR=7.095; RR=1.508; sensitivity=0.316 and P<0.0001)) for male patients. Highly cooked food (OR=2.485; RR=1.126; sensitivity=0.418 and P=0.004)) and also genetic inheritance (OR=1.93; RR=1.335; sensitivity=0.163 and P=0.138) demonstrated significant correlation with lung cancer as risk factors after these two and alcohol consumption was not prevalent. On the other hand, for female patients, tobacco leaf intake represented the highest risk (OR=2.00; RR=1.429; sensitivity= 0.667 and P=0.5603) while genetic inheritance and highly cooked food also correlate with lung cancer but not so significantly. Socio- economic status and education level also play important roles in causing lung cancer. Some 78.5% male and 83.3% of female cancer patients were rural residents, while 58.2% lived at the margin or below the poverty line. Most male (39.8%) and female (50.0%) patients had completed only primary level education, and 27.6% male and 33.3% female patients were illiterate. Smoking was found to be more prevalent among the less educated persons. CONCLUSIONS: The results obtained in this study indicate the importance of creating awareness about lung cancer risk factors among Bangladeshi people and making appropriate access to health services for the illiterate, poor, rural people.