ORCID Profile
0000-0003-0182-5269
Current Organisations
Brigham and Women's Hospital
,
Harvard School of Public Health
,
Aichi Cancer Center Research Institute
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Publisher: Elsevier BV
Date: 07-2020
Publisher: Oxford University Press (OUP)
Date: 07-09-2020
Abstract: We hypothesized that the associations between coffee intake and colorectal cancer (CRC) incidence might differ by immune cell densities in CRC tissue. Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of coffee intake with incidence of CRC classified by intraepithelial or stromal T-cell subset densities by multiplex immunofluorescence assay for CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3. We applied an inverse probability-weighted Cox proportional hazardsregression model to control for selection bias and potential confounders. During follow-up of 133 924 participants (3 585 019 person-years), we documented 3161 incident CRC cases, including 908 CRC cases with available data on T-cell densities in tumor tissue. The association between coffee intake and CRC was not statistically significantly different by intraepithelial or stroma T-cell subset (Pheterogeneity & .38). Hence, there is no sufficient evidence for differential effect of coffee intake on incidence of CRC subtypes classified by T-cell infiltrates.
Publisher: Oxford University Press (OUP)
Date: 14-05-2020
Abstract: Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue. Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses’ Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn’s-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer–specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided Pinteraction = .009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction. The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.
Publisher: Wiley
Date: 21-01-2018
DOI: 10.1111/CAS.13470
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2020
DOI: 10.1158/1078-0432.CCR-20-0071
Abstract: Although high T-cell density is a well-established favorable prognostic factor in colorectal cancer, the prognostic significance of tumor-associated plasma cells, neutrophils, and eosinophils is less well-defined. We computationally processed digital images of hematoxylin and eosin (H& E)–stained sections to identify lymphocytes, plasma cells, neutrophils, and eosinophils in tumor intraepithelial and stromal areas of 934 colorectal cancers in two prospective cohort studies. Multivariable Cox proportional hazards regression was used to compute mortality HR according to cell density quartiles. The spatial patterns of immune cell infiltration were studied using the GTumor:Immune cell function, which estimates the likelihood of any tumor cell in a s le having at least one neighboring immune cell of the specified type within a certain radius. Validation studies were performed on an independent cohort of 570 colorectal cancers. Immune cell densities measured by the automated classifier demonstrated high correlation with densities both from manual counts and those obtained from an independently trained automated classifier (Spearman's ρ 0.71–0.96). High densities of stromal lymphocytes and eosinophils were associated with better cancer-specific survival [Ptrend & 0.001 multivariable HR (4th vs 1st quartile of eosinophils), 0.49 95% confidence interval, 0.34–0.71]. High GTumor:Lymphocyte area under the curve (AUC0,20μm Ptrend = 0.002) and high GTumor:Eosinophil AUC0,20μm (Ptrend & 0.001) also showed associations with better cancer-specific survival. High stromal eosinophil density was also associated with better cancer-specific survival in the validation cohort (Ptrend & 0.001). These findings highlight the potential for machine learning assessment of H& E-stained sections to provide robust, quantitative tumor-immune biomarkers for precision medicine.
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/2326-6066.CIR-20-0527
Abstract: Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
Publisher: Oxford University Press (OUP)
Date: 15-07-2021
DOI: 10.1093/JNCI/DJAB142
Abstract: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates. Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability–weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided. During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = .003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend & .009, with an α level of .005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages. The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
Publisher: BMJ
Date: 04-2021
Abstract: Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood. We used multiplexed immunofluorescence combined with digital image analysis to identify CD14 + monocytic and CD15 + granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1–Q4) of myeloid cell densities. Immune cell–tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius. Higher intraepithelial ( P trend =0.0002 HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal ( P trend .0001 HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14 + HLA-DR + cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14 + HLA-DR − cells were associated with higher colorectal cancer-specific mortality ( P trend =0.0003 HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15 + cells were located closer to tumor cells than CD14 + cells, and CD14 + HLA-DR + cells were closer to tumor than CD14 + HLA-DR − cells (p .0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14 + HLA-DR + cell versus CD14 + HLA-DR − cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality ( P trend .0001 HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57). Myeloid cell populations occur in spatially distinct distributions and exhibit ergent, subset-specific prognostic significance in colorectal cancer, with mature CD14 + HLA-DR + and immature CD14 + HLA-DR − monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2019
DOI: 10.1158/1055-9965.EPI-19-0389
Abstract: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium. The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty. We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (& .5 kg/m2: HR = 0.80, 95% CI: 0.52–1.24 18.5–24.9 kg/m2: reference 25.0–29.9 kg/m2: HR = 1.17, 95% CI: 0.94–1.47 ≥30 kg/m2: HR = 1.61, 95% CI: 0.99–2.64, Ptrend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality. This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations. This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations.
Publisher: American Association for Cancer Research (AACR)
Date: 25-02-2021
DOI: 10.1158/1078-0432.CCR-20-4009
Abstract: While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell–mediated antitumor immunity, the specific T-cell subsets involved remain uncertain. We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum–positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets. The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47 95% confidence interval (CI), 0.28–0.79, for F. nucleatum–high vs. -negative category Ptrend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52 95% CI, 0.32–0.85 Ptrend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs. The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.
No related grants have been discovered for Tomotaka Ugai.