Immunologic tumor microenvironment modulators for turning cold tumors hot.

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune-resistant tumors.

The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system.

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation, growth, and therapy resistance. The hallmarks of cancer-fibroblast interactions, consisting of caveolin 1 (Cav1) and mono-carboxylate transporter 4 (MCT4) (metabolic coupling markers), along with IL-6, TGFß, and lactate secretion, are considered robust biomarkers predicting recurrence and metastasis. In order to promote a novel phenotype in normal fibroblasts, we predicted that breast cancer cells could be able to cause loss of Cav1 and increase of MCT4, as well as elevate IL-6 and TGFß in nearby normal fibroblasts. We created a co-culture model using breast cancer (4T1) and normal fibroblast (NIH3T3) cell lines cultured under specific experimental conditions in order to directly test our theory. Moreover, we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cav1 and gain of MCT4 in adjacent fibroblasts and increase lactate secretion. These results were validated using the monoculture of each group separately as a control. In this system, we show that metformin inhibits IL-6 and TGFß secretion and re-expresses Cav1 in both cells. However, MCT4 and lactate stayed high after treatment with metformin. In conclusion, our work shows that co-culture with breast cancer cells may cause significant alterations in the phenotype and secretion of normal fibroblasts. Metformin, however, may change this state and affect fibroblasts' acquired phenotypes. Moreover, mitochondrial inhibition by metformin after 8 days of treatment, significantly hinders tumor growth in mouse model of breast cancer.

Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.

BACKGROUND: Chemoresistance is a challenging barrier to cancer therapy, and in this context, the role of mitochondria is significant. We put emphasis on key biological characteristics of mitochondria, contributing to tumor escape from various therapies, to find the "Achilles' Heel" of cancer cells for future drug design. RECENT FINDINGS: The mitochondrion is a dynamic organelle, and its existence is important for tumor growth. Its metabolites also cooperate with cell signaling in tumor proliferation and drug resistance. CONCLUSION: Biological characteristics of this organelle, such as redox balance, DNA depletion, and metabolic reprogramming, provide flexibility to cancer cells to cope with therapy-induced stress.

Perceived stress, anxiety, and depression in women with breast cancer: CIBC study.

BACKGROUND: Many breast cancer (BC) patients experience psychological reactions and may have psychiatric morbidities, especially anxiety and depressive disorders. The aim of this study was to evaluate perceived stress and factors affecting this stress in women with BC in Isfahan. MATERIAL AND METHODS: This analytical cross-sectional study was carried out among 197 females with BC who were newly diagnosed and referred to Isfahan Cardio-Oncology Clinic. Stress was measured by the Perceived Stress Scale Standard questionnaire. Generalized linear models (GLMs) with gamma distribution and Log Link Function were used for data analyzing. RESULTS: The mean age of the patients was 48.9 ± 10.9 years, and mean perceived stress in patients was 42.8 ± 16.5. The GLMs with Gamma distribution and Log Link Function showed interaction between anxiety and surgical type and also between depression and surgical type. Patients perceived stress with anxiety*nonsurgery were significantly 2.5% higher than normal anxiety and none surgery (P = 0.004), and patients with depression*lumpectomy had significantly 2% higher stress score compared to normal depression and nonsurgery (P =0.003). CONCLUSIONS: Early detection of anxiety and depression can contribute to managing the stress. Coordination between psychologists and oncologists in care and treatment of these patients is important for pursuing treatment and following the recommendations of doctors and ultimately affect the morbidity and survival in BC patients.

The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors.

Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.

Rational, Design and Preliminary Results of a Cohort Study on Breast and Colorectal Cancer to Develop a Risk Assessment Model to Predict Future Cardiovascular Events. "Cardio Vascular Events in Breast and Colorectal Cancers (CIBC) Study".

Breast cancer (BC) and colorectal cancer (CRC) are among the most common cancers in Iran. We aimed to develop a risk assessment model to predict the development of cardiovascular events in these patients by performing a 5 year prospective cohort study on a newly diagnosed patients with BC or CRC before they receive any treatment. A multi-center prospective cohort study of 2700 newly diagnosed BC and CRC patients has been started in Iran since 2019 and will be continued until 2024. Demographics, socioeconomic status, life style behaviors, psychological characteristics and type of cancer treatments will be collected by standard questionnaires and blood pressure, obesity indices will be measured. Blood sampling, ECG, and echocardiography will be done in all patients at base line, 6 and 12 months, then at annual basis for five years. Incidence of heart failure, acute coronary syndrome, stroke and CVD related death are the primary outcome of this study. In this preliminary analysis, 70 patients with BC and 30 patients with CRC were enrolled in this study from April 2019 to November 2019. Mean age of BC and CRC patients was 48 ± 10.5 and 61 ± 13.2 respectively. 98.6% of patients in BC group and 60% of CRC groups were female. This study will be a platform for other cancers to develop CVD risk assessment charts that can cover other cancers. Patients who lie in the high risk category according to the newly developed risk assessment chart, should receive special management and preventive interventions.

Validation of a newly developed questionnaire regarding clinical history in patients with breast and colorectal cancers.

BACKGROUND: Understanding the close interaction between the specialties of cardiology and oncology is necessary for early detection of cardiovascular disease (CVD) events in cancer patients. For the risk assessment of CVD in Breast and Colorectal Cancers (CIBC) study, in the current study we aimed to validate a questionnaire for the assessment of clinical history in patients with breast cancer and colorectal cancer (CRC). METHODS: We determined the content validity of the questionnaire using the 2 indexes of content validity ratio (CVR) and content validity index (CVI) to examine the specificity, simplicity, clarity, and transparency of the items. Content validity assessment was performed through a panel of experts including 2 oncologists, 5 cardiologists, 2 general practitioners, and 1 epidemiologist. The reliability of the questionnaire was estimated using Cronbach's alpha coefficient in 50 patients. Intraclass correlation coefficient (ICC) was used to examine the reproducibility of the questionnaire during 1 week. RESULTS: The CRC and breast cancer questionnaire were designed with 16 and 32 questions, respectively. To obtain acceptable CVR, 5 and 11 questions were removed from the CRC and breast cancer questionnaires, respectively. Cronbach's alpha was 0.70 in the breast cancer questionnaire and 0.94 in the CRC questionnaire. All questions had a CVI of higher than 80%. The ICC in the breast cancer questionnaire ranged between 0.71 and 0.96 and in CRC questionnaire ranged between 0.78 and 0.98. CONCLUSION: The validity and reliability of our newly developed questionnaire was desirable. The reliability of the breast cancer questions was acceptable and that of the CRC questions was excellent. Thus, thus questionnaire can be used in this group of patients regardless of whether the goal is cardiac care or not.

Effects of a comprehensive cardiac rehabilitation program on quality of life in patients with coronary artery disease.

BACKGROUND: Health-related quality of life is an important factor to evaluate effects of different interventions in cardiovascular diseases. Improvement in quality of life (QOL) is an important goal for individuals participating in cardiac rehabilitation (CR) programs. The purpose of this study was to assess the impact of comprehensive CR on QOL in patients with cardiovascular disease (CAD). METHODS: In this quasi-experimental before-after study, the files of 100 patients with CAD who were referred to rehabilitation department of Isfahan Cardiovascular Research Institute were studied using a consecutive sampling method. Data collection was performed from the patient's files including their demographics, ejection fraction, functional capacity, and resting heart rate. All patients participated in a comprehensive CR program and completed the validated questionnaire Short-Form 36 Health Status Survey (SF-36), before and after CR program. Data was analyzed based on sex and age groups (≥ 65 and < 65 years) using independent t-test and paired t-test (to compare variables between groups and before and after CR, respectively). RESULTS: After CR, scores of all physical domains of the SF-36 including physical function (PF), physical limitation (PL), body pain (BP) and vitality (V) in addition to general health (GH) were significantly improved in all patients (P < 0.05) compared to the baseline. Patients with age < 65 years had greater improvements in mental health (MH) and social function (SF) than patients with age ≥ 65 years (P < 0.05). Women had greater improvement in PF, V and MH compared to men (P < 0.05). CONCLUSION: These results indicated that CR can improve QOL in cardiac patients especially in women. Elderly patients get benefit the same as other patients in physical domains.

The effect of the cardiac rehabilitation program on obese and non-obese females with coronary heart disease.

INTRODUCTION: Obesity is strongly associated with coronary heart disease and it is known as an independent risk factor. So, the aim of this study was to investigate the effects of phase II comprehensive cardiac rehabilitation program on obesity indexes, functional capacity, lipid profiles, and fasting blood sugar in obese and non-obese female patients with coronary heart disease and to compare changes in these groups. MATERIALS AND METHODS: Two hundred and five women with coronary heart disease participated in our study. At the beginning of study, body mass index, functional capacity, and lipid profiles and fasting blood sugar were evaluated; then, these patients were divided into two groups, patients who had BMI≥30 were known as obese and who had BMI<30 were known as non-obese patients. All of them completed the period of cardiac rehabilitation program, and 2 months later, all risk factors were examined for the second time in each group. Data were analyzed with SPSS software version 15. For comparing the mean of outcomes, independent t-tests and paired t-tests were used. RESULTS: Data revealed that unless in weight (P=0.00) and functional capacity (P=0.001), there were no significant differences in obese and non-obese female patients, at baseline. As a result of the cardiac rehabilitation program, both groups had significant improvement in functional capacity (P=0.00), weight reduction (P=0.00), triglyceride (P=0.01 and P=0.02, respectively), low-density lipoprotein cholesterol (P=0.01), and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (P=0.00 and P=0.003, respectively). As well, significant improvement was observed in high-density lipoprotein (P=0.01) only in obese female, and non-obese female had significant differences in total cholesterol (P=0.003). However, there were not significant changes in total cholesterol (P=0.05) and fasting blood sugar (P=0.09) in obese female. Also, non-obese females didn't have favorable differences in high-density lipoprotein cholesterol (P=0.23) and fasting blood sugar (P=0.13). In addition, comparing two groups didn't show any significant differences in each risk factors except BMI (P=0.03). CONCLUSION: Our study revealed that comprehensive cardiac rehabilitation program results in significant improvement in cardiovascular risk factors and functional capacity at all levels of BMI in female with coronary heart disease.

The effects of cardiac tertiary prevention program after coronary artery bypass graft surgery on health and quality of life.

OBJECTIVES: Cardiac tertiary prevention programs intend to support the recovery course following coronary artery bypass grafting (CABG). We investigated the effects of attendance at cardiac rehabilitation (CR) programs following CABG on patients' mortality, morbidity and health related quality of life. METHODS: Eighty patients who underwent CABG were selected in a way that half of them had attended a cardiac rehabilitation program and the other half had not. Health related quality of life (HRQoL) was measured using the Short Form 36 (SF-36) questionnaire at a mean of 23.4 months postoperatively. Severity of cardiac symptoms on the basis of the New York Health Association (NYHA), the occurrence of any neurological symptoms, hospitalization and restoration of patients to their previous level of performance in social activities were assessed after CABG surgery. RESULTS: There were no deaths. There were no differences in postoperative NYHA scores, neurological symptoms, and hospitalization. Three of the eight health domains measured by SF-36, namely general health (P = 0.010), physical function (P = 0.002), and mental health (P < 0.001), showed significantly better values for attendants than non-attendants. Rehabilitation participants returned to their previous level of performance in social activities more than their control counterparts. CONCLUSIONS: Higher general health scores (SF-36) were associated with attendance at CR programs. The findings of this study provide rationale to consider a broader scope of physiological and psychosocial parameters to predict outcomes of CABG surgery.