The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.

https://science.sciencemag.org/content/sci/313/5795/1960.full.pdf

Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

http://science.sciencemag.org/content/sci/331/6024/1565.full.pdf

Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion

Infiltrating stromal and immune cells form the major fraction of normal cells in tumour tissue and not only perturb the tumour signal in molecular studies but also have an important role in cancer biology. Here we describe 'Estimation of STromal and Immune cells in MAlignant Tumours using Expression data' (ESTIMATE)--a method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples. ESTIMATE scores correlate with DNA copy number-based tumour purity across samples from 11 different tumour types, profiled on Agilent, Affymetrix platforms or based on RNA sequencing and available through The Cancer Genome Atlas. The prediction accuracy is further corroborated using 3,809 transcriptional profiles available elsewhere in the public domain. The ESTIMATE method allows consideration of tumour-associated normal cells in genomic and transcriptomic studies. An R-library is available on https://sourceforge.net/projects/estimateproject/.

/pdf/inferring-tumour-purity-and-stromal-and-immune-cell-3qvnp398w9.pdf

Inferring tumour purity and stromal and immune cell admixture from expression data

Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.

The immune contexture in human tumours: impact on clinical outcome

Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

/pdf/sex-differences-in-immune-responses-5lxzp3yqfg.pdf

Sex differences in immune responses

A microchip that integrates the sol-gel affinity column of a SELEX system is developed. This microchip includes electric heaters for individual heat elution from sol-gels which contain target molecules. To test the microfluidic system for SELEX compatibility, a known aptamer targeting TBP was delivered, then eluted from solgels and collected for RT-PCR. We also demonstrated the multiplex SELEX in this microfluidic system by well-defined aptamers that bind either TBP and TFIIB. We could specifically bind and elute the corresponding aptamers from each target protein sol-gel. Comparing to the conventional SELEX, our microfluidic SELEX system improved cycle efficiency by 2 cycles.

SELEX-on-a-chip: Microchip integration of the sol-gel derived affinity column for monitoring RNA-protein interaction

Age-specific Physical Activity And Prostate Cancer Risk Among White Men And Black Men: 885

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Objective. Ecological studies conducted in the United States and globally have shown an inverse association between levels of solar ultraviolet irradiance and kidney cancer incidence, suggesting that vitamin D, which is obtained from exposure to ultraviolet light (sunlight), may be associated with a reduced risk of kidney cancer. However, results from two prospective cohort and two case-control studies focusing on dietary vitamin D reported no statistically significant association with the development of kidney cancer. Thus, the purpose of this study was to examine the association between circulating 25-hydroxyvitamin D (25(OH)D), the accepted biomarker for vitamin D status, and the development of kidney cancer within a large pooled nested case-control study carried out as part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP).

Methods. Kidney cancer cases (n = 775) and age-, sex-, race-, and season-matched controls (n = 775) were identified from eight prospective cohort studies participating in the VDPP. Data on potential confounders were obtained and harmonized by a central data coordinating center. Serum/plasma samples were assayed for 25(OH)D at Heartland Assays, Inc using the DiaSorin LIAISON 25(OH)D TOTAL assay, a direct, competitive chemiluminescence immunoassay. Clinically-defined cutpoints suggesting deficient, insufficient, and sufficient 25(OH)D concentrations were used to analyze the association between high and low circulating 25(OH)D and kidney cancer, with 50 to <75nmol/L chosen as the reference category. The main analyses were conducted using conditional logistic regression models adjusting for matching variables and potential confounders such as high blood pressure and body mass index.

Results. Neither low nor high concentrations of circulating 25(OH)D were significantly associated with kidney cancer risk overall or the renal cell carcinoma subtype. Sex-specific analyses showed, however, that high concentrations of 25(OH)D (>75 nmol/l) were associated with a non-significant increased risk of kidney cancer among males (reference: 50 to <75 nmol/l) (OR=1.52, 95% CI: 0.95, 2.41) and a statistically significant decreased risk among females (OR=0.31, 95% CI: 0.12, 0.85) (interaction P-value = 0.42). Conclusions. The findings from this consortium-based study indicate that vitamin D is not associated with the risk of kidney cancer or the renal cell carcinoma subtype, although additional investigation of the possible modification of the association by sex is warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2800.

Abstract 2800: The association between circulating 25-hydroxyvitamin D and the development of kidney cancer in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

BACKGROUND. Reactive oxygen species (ROS) are known to react with DNA resulting in the transformation of normal epithelium to a malignant phenotype. While one functional variant in catalase (CAT) has been shown to be pertinent to breast cancer risk, few other polymorphisms in this gene have been assessed. Genetic variation in CAT or other genes in the oxidative stress pathway may mediate the carcinogenic effect of ROS produced by recreational physical activity (RPA) or result in adaptation of antioxidant capacity. METHODS. We investigated the association between three polymorphisms in CAT (rs4756146, rs2284365, rs480575) and breast cancer risk. We also characterized the joint effects of RPA with CAT, and with other functional oxidative stress variants (COMT, GPX, GSTA1, GSTM1, GSTP1, GSTT1, MnSOD, MPO, and UGT2B7) on breast cancer risk. Data were from the Long Island Breast Cancer Study Project, a population-based case-control study with interview and biomarker data available on 1102 cases and 1141 controls. Adjusted unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS. The presence of at least one CAT variant allele in rs4756146 was associated with a 23% decreased risk of postmenopausal breast cancer (95% CI=0.59-0.99). While rs2284365 and rs480575 were not associated with breast cancer risk, interaction between the two was evident on the multiplicative scale (likelihood ratio test p=0.087) indicating possible antagonism for these CAT polymorphisms. Further, upon combining the CAT genotypes, we observed a positive association between breast cancer risk and the number of putative high-risk alleles. Women with ≤ 4 high-risk alleles were at a 44% increased risk of breast cancer (95% CI=1.04-2.00) compared to women with ≤ 2 high-risk alleles. Finally, two polymorphisms (CAT rs1001179 and GSTP1 rs1695) among the oxidative stress genes considered were found to interact multiplicatively with postmenopausal RPA. Variant alleles in CAT antagonistically reversed the effect of high RPA on breast cancer risk (p=0.043) while variant alleles in GSTP1 synergistically enhanced the effect of low RPA on breast cancer risk (p=0.006). CONCLUSIONS. This study suggests that postmenopausal breast cancer risk may be decreased among women with one variant CAT allele in rs4756146. Risk may be elevated when considering combined effects of multiple high risk alleles in CAT. Variants in both CAT and GSTP1 may modify the association between RPA and breast cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2601. doi:1538-7445.AM2012-2601

Abstract 2601: Polymorphisms in oxidative stress genes, physical activity and breast cancer risk

Dear Editor, Dupilumab is a human monoclonal antibody that targets the interleukin (IL)-4 receptor subunit α of IL-4 and IL-13 receptors. Recently, dupilumab has successfully been used to treat severe atopic dermatitis (AD). However, it was not always effective as expected and adverse events such as facial erythema also occurred. In that cases, previous studies introduced the combination therapy of dupilumab and systemic immunosuppressants to improve efficacy and mitigate the side effects. However, there have been many cases where patients who are using dupilumab had side effects on immunosuppressants when they used it before. Baricitinib, a new therapeutic agent which inhibits Janus kinase 1 & 2, is an excellent alternate for immunosuppressants with the advantage of lesser complication. We report successfully treated cases with a combination of dupilumab with baricitinib (Table 1). A first case is a 31-year-old man, who had been treated with dupilumab for severe atopic dermatitis for more than 3 years. The disease activity was well-controlled to the extent that the eczema area severity index (EASI) score was kept below 1 after the administration of dupilumab. However, he experienced a temporal aggravation of AD symptoms every summer when the exposure to air conditioners is often. With informed consent, we prescribed baricitinib, 4 mg once a day (Figure 1A,B). A second case is a 26-year-old man who showed sudden deterioration. He already administered dupilumab 16 times with a good response. But he started to worsen at some point, and on the 18th day of administration, he could not keep the previously achieved EASI 75. Baricitinib 4 mg was added to improve this condition (Figure 2A,B). A third case is a 22-year-old man, who did not get enough effect with dupilumab. He was treated with dupilumab for more than a year; however, he couldn't achieve EASI 75. Since his EASI score did not fall below five and eczema on his foot caused consistent inconvenience due to fissure and pain, we added baricitinib 4 mg daily (Figure 3A,B). The last case is a 36-year-old woman who had just been started to use dupilumab for 4 weeks. Her AD symptoms did not improve after the administration of dupilumab, which was reflected in no change in all measures. Even her facial erythema worsened, and insomnia occurred due to aggravated itching. To ease the discomfort of the healing process, we decided to prescribe baricitinib 4 mg every day (Figure 4A,B). We added baricitinib on patients with (1) temporal aggravation, (2) insufficient effect, and (3) hyper-eosinophilia during dupilumab treatment. Baricitinib was added to these patients, and after 4 weeks, all patients experienced an improvement in EASI score. However, improvement in subjective measures was varied. On the other hand, in two cases, hyper-eosinophilia improved after the use of baricitinib. Even though dupilumab induced hyper-eosinophilia could be transitory, this finding suggests the possibility of baricitinib as another option for alleviating dupilumab induced hyper-eosinophilia. Additionally, patients maintained baricitinib for 1–2 months until the aggravated symptoms recovered, and discontinued after tapering with 2 mg. There were no adverse events observed until the drug discontinuation.

Jiyoung Ahn

Papers

SELEX-on-a-chip: Microchip integration of the sol-gel derived affinity column for monitoring RNA-protein interaction

Age-specific Physical Activity And Prostate Cancer Risk Among White Men And Black Men: 885

Abstract 2800: The association between circulating 25-hydroxyvitamin D and the development of kidney cancer in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Abstract 2601: Polymorphisms in oxidative stress genes, physical activity and breast cancer risk

The effect of baricitinib add‐on therapy in atopic dermatitis patients treated with dupilumab