Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer

Jiménez-Rodríguez, Rosa M; Patil, Sujata; Keshinro, Ajaratu; Shia, Jinru; Vakiani, Efsevia; Stadler, Zsofia K.; Segal, Neil H.; Yaeger, Rona; Konishi, Tsuyoshi; Shimada, Yasuhiro; Widmar, Maria; Wei, Iris; Pappou, Emmanouil; Smith, J. Joshua; Nash, Garrett M.; Paty, Philip B.; García-Aguilar, Julio; Weiser, Martin R.

doi:10.1080/2162402x.2020.1841948

Cited by 7 publications

(8 citation statements)

References 35 publications

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“…TIL count within the tumor was quantified as previously described, by quantifying lymphocytes in five high-power fields in an area determined to have the highest concentration of TIL. 18 A tumor was classified as TIL-high if the mean number of TILs per high-power field (HPF) was ≥4, as previously described. 19 …”

Section: Methodsmentioning

confidence: 99%

“… 12–17 Immunotherapy achieves better outcomes in patients with dMMR colon cancer than chemotherapy 9 , 12 , 15 and is now the first-line treatment for metastatic disease. Not all dMMR tumors are enriched in TILs, 18–20 and some MMR-proficient (pMMR) tumors have high levels of TILs, which appear to be associated with the underlying genomics. 18 , 19 pMMR tumors with high levels of TILs have been shown to respond well to immunotherapy, 15 , 17 , 21 and this finding has led to a clinical trial (NCT04262687) evaluating the effectiveness of immune checkpoint blockade in patients with these tumors.…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

et al. 2022

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Colon tumors with deficient DNA mismatch repair (dMMR) are generally infiltrated by T cells more densely than tumors with proficient mismatch repair (pMMR). However, high numbers of tumor-infiltrating lymphocytes (TILs) are found in select pMMR tumors, and low numbers of TILs are seen in select dMMR tumors. In this study, we compared T-cell repertoires in 20 pMMR and 27 dMMR colon tumors with high and low TIL counts. We found that T cells in dMMR tumors are more clonal and their repertoire is less rich compared with T cells in pMMR tumors. In the dMMR group, T cells in TIL-high tumors were more clonal and their repertoire was less rich compared with T cells in TIL-low tumors, but in the pMMR group, T-cell diversity in TIL-high tumors was comparable to T-cell diversity in TIL-low tumors. These findings suggest that T cells clonally expand in dMMR tumors, possibly in response to MMR deficiency-induced tumor neoantigens.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

et al. 2022

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“…Tumors were staged according to American Joint Committee on Cancer and categorized as right sided (cecum, ascending colon, or transverse colon) or left sided (descending colon, sigmoid, or rectosigmoid). The level of TIL was quantified according to a protocol proposed by the College of American Pathologists 14 and as previously outlined, 10,15,16 with a slight modification. Briefly, TIL within the epithelial compartment were identified on standard hematoxylin-eosin-stained slides (without specific T-cell markers).…”

Section: Pathology Analysismentioning

confidence: 99%

“…5,9 In a recent analysis, we found that the number of TIL per high-power field ranges greatly in both MSI and MSS colon tumors, with up to 18% of MSI tumors containing low levels of TIL and up to 36% of MSS tumors containing high levels of TIL. 10 Interest in TIL has grown significantly, as they are prognostic of survival outcomes [10][11][12] and may be predictive of response to immunotherapy in colorectal cancer. 13 In this study, we used histopathologic analysis and next-generation sequencing to characterize the relationship between TIL and oncogenic signaling pathway alterations in MSI, MSS, or mutant POLE/POLD1 (POLE/D1) colon cancer.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

Keshinro

Vanderbilt

Kim

et al. 2021

JCO Precision Oncology

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PURPOSE To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb ( P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.

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“…[12] CIBERSORT can assess the tumor-in ltrating immune cells in tumor, through which prognosis models of immune cells in ltration are constructed in several types of cancer including breast, gastric and lung cancer [13][14][15] . As a signi cant part of tumor-in ltrating immune cells, tumor-in ltrating lymphocytes (TILs) have been shown to indicate the clinical prognosis in colon cancer [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

A Tumor-Infiltrating Lymphocyte-Based Risk Model Predicts Prognosis of Colon Cancer

Sui

Zhu

et al. 2021

Preprint

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Tumor-infiltrating lymphocytes are relevant to the tumor prognosis and response to immunotherapy in colon cancer. The gene expression data of colon cancer was obtained from the cancer genome atlas (TCGA) database and the components of immune cell types were analyzed by CIBERSORT. Selection operator (LASSO) and multivariate Cox regression filtered immune cells and selected the most significant cell types to construct an immune risk model including memory B cells, plasma cells, T follicular helper (Tfh) cells, M0 macrophages and resting dendritic cells. Receiver operating characteristic (ROC) curves were used to verify the sensitivity and specificity of the model, which was validated in Gene Expression Omnibus (GEO) dataset. Combined with the clinical traits, a nomogram was established to predict the prognosis of colon cancer. According to function analyses through weighted correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA), tumor-infiltrating immune cells showed significant importance in tumor immune-associated regulation, especially the adhesion, migration and invasion in colon cancer.

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Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer

Cited by 7 publications

References 35 publications

Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

A Tumor-Infiltrating Lymphocyte-Based Risk Model Predicts Prognosis of Colon Cancer

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