Tumor-Infiltrating Lymphocytes, Crohn’s-Like Lymphoid Reaction, and Survival From Colorectal Cancer

Rozek, Laura S.; Schmit, Stephanie L.; Greenson, Joel K.; Tomsho, Lynn P.; Rennert, Gad; Rennert, Gad; Gruber, Stephen B.

doi:10.1093/jnci/djw027

Cited by 180 publications

(175 citation statements)

References 42 publications

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“…Integrated analysis of tumor molecular features and immune cells in the tumor microenvironment is increasingly important, 52–54 because ample evidence indicates bidirectional influences of tumor molecular alterations and immune response to tumor. 55, 56 Considering the relationship between tumor characteristics and immunity, we further investigated whether the observed association of pro-inflammatory diets with cancer containing little or no peritumoral lymphocytic reaction might be due to a potential association between pro-inflammatory diets and specific tumor molecular subtypes such as those classified by MSI, CIMP, BRAF mutation, or PTGS2 expression status.…”

Section: Discussionmentioning

confidence: 99%

Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor

et al. 2017

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Background & Aims Dietary patterns affect systemic and local intestinal inflammation, which have been linked to colorectal carcinogenesis. Chronic inflammation can interfere with the adaptive immune response. We investigated whether the association of a diet that promotes intestinal inflammation with risk of colorectal carcinoma was stronger for tumors with lower lymphocytic reactions than tumors with higher lymphocytic reactions. Methods We collected data from the molecular pathological epidemiology databases of 2 prospective cohort studies: the Nurses’ Health Study (since 1976) and the Health Professional Follow-up Study (since 1986). We used duplication-method time-varying Cox proportional cause-specific hazards regression to assess the association of empirical dietary inflammatory pattern (EDIP) score (derived from food frequency questionnaire data) with colorectal carcinoma subtype. Foods that contribute to high EDIP scores include red and processed meats, refined grains, carbonated beverages, and some vegetables; foods that contribute to low EDIP scores include beer, wine, coffee, tea, yellow and leafy vegetables, and fruit juice. Colorectal tissue samples were analyzed histologically for patterns of lymphocytic reactions (Crohn’s-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes). Results During follow up of 124,433 participants, we documented 1311 incident colon and rectal cancer cases with available tissue data. The association between the EDIP and colorectal cancer risk was significant (Ptrend = .02), and varied with degree of peritumoral lymphocytic reaction (Pheterogeneity < .001). Higher EDIP scores were associated with increased risk of colorectal cancer with an absent or low peritumoral lymphocytic reaction (highest vs lowest EDIP score quintile hazard ratio = 2.60; 95% CI, 1.60–4.23; Ptrend < .001) but not risk of tumors with intermediate or high peritumoral lymphocytic reaction (Ptrend > .80). Conclusions In a prospective cohort study, we associated inflammatory diets with a higher risk of colorectal cancer subtype that contains little or no peritumoral lymphocytic reaction. These findings suggest that diet-related inflammation might contribute to development of colorectal cancer, by suppressing the adaptive anti-tumor immune response.

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Section: Discussionmentioning

confidence: 99%

Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor

et al. 2017

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“…The assessment of host immunity against colorectal cancer in the tumor microenvironment is increasingly important in translational research and routine clinical practice for tumor classification (36,37). A strong histological lymphocytic reaction to colorectal carcinoma has been associated with better patient survival (15,16). These data indicate that histopathological characterization of lymphocytic infiltrates in cancer tissue is of value when assessing the magnitude of antitumor immune response to colorectal malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…Crohn’s-like lymphoid reaction is characterized by the transmural presence of discrete lymphocytic aggregates with tertiary lymphoid structures, including germinal centers, T-cell-rich area, and high endothelial venules (38–40). Previous studies have linked strong Crohn’s-like lymphoid reaction to favorable outcomes in patients with colorectal carcinoma (15,16,38,39). Tertiary lymphoid tissues, such as Crohn’s-like lymphoid reaction, has a potential role in maintaining adaptive immune responses to colorectal cancer, as a local source of antigen-specific effector B and T cells (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Potent lymphocytic reactions and higher density of T cells in colorectal carcinoma tissue have been associated with better patient survival, supporting a major role of antitumor immunity in inhibiting tumor progression (11–16). Previous studies have linked intense lymphocytic reaction to colorectal cancer to high tumor neoantigen load and certain tumor molecular characteristics, including high-level microsatellite instability (MSI-high) (15–18). Evidence attests to the important role of CD274 (PD-L1) in suppressing antitumor immunity in a number of tumor types including colorectal cancer (1–3).…”

Section: Introductionmentioning

confidence: 99%

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Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer

Masugi

Nishihara

Hamada

et al. 2017

Cancer Immunology Research

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Expression of the immune-checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell–mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by immunohistochemistry in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2–expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn’s-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn’s-like lymphoid reaction (Ptrend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn’s-like lymphoid reaction, a multivariable odds ratio in the highest (vs lowest) quartile of the percentage of PDCD1LG2–expressing tumor cells was 0.38 (95% confidence interval, 0.22–0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival (Ptrend>0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn’s-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2–expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis.

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“…In addition to identifying dMMR/MSI-high colorectal carcinomas, TILs have also been shown to have important prognostic value in all colorectal carcinomas, regardless of MSI status [60]. Both semi-quantitative H&E-based scoring and digital quantitation of TILs on IHC have received much attention in the literature.…”

Section: Tils In Colorectal Carcinomamentioning

confidence: 99%

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

571

366

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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Tumor-Infiltrating Lymphocytes, Crohn’s-Like Lymphoid Reaction, and Survival From Colorectal Cancer

Abstract: TILs and CLR are both prognostic indicators for CRC after adjusting for traditional prognostic indicators.

Cited by 180 publications

References 42 publications

Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor

Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor

Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer

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