Regulatory T Lymphocytes Are Associated with Less Aggressive Histologic Features in Microsatellite-Unstable Colorectal Cancers

Tougeron, David; Maby, Pauline; Elie, Nicolas; Fauquembergue, Emilie; Pessot, Florence Le; Cornic, Marie; Sabourin, Jean‐Christophe; Michel, Pierre; Frébourg, Thierry; Latouche, Jean-Baptiste

doi:10.1371/journal.pone.0061001

Cited by 24 publications

(15 citation statements)

References 39 publications

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“…However, NMD is not a completely efficient mechanism in tumor cells (36,37) and, moreover, it has been shown that a major source of antigenic peptides for the MHC-I pathway is the pioneer round of mRNA translation that precedes putative NMD (38). CD8 þ TIL density was not correlated with prognosis in these independent series of patients with MSI colorectal cancer (20). Our series might be too small for robust survival statistical analysis, but there could also be a balance between beneficial effects of the immune response and deleterious effects of some studied mutations, many of the studied genes being tumor suppressor genes.…”

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confidence: 84%

Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

et al. 2015

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Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8 þ T cells. However, there has yet to be a clear link established between CD8 þ TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3 þ , CD8 þ , and FOXP3 þ TIL densities were quantitated. We found that CD8 þ TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8 þ T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome. Cancer Res; 75(17); 3446-55. Ó2015 AACR.

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confidence: 84%

Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

et al. 2015

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“…Two fields of view within a 0·6‐mm 2 region were chosen at random to count TILs and stromal lymphocytes separately, as described previously ( Fig . S1, supporting information). The mean CD8+ cell density was calculated in the tumour andstromal areas.…”

Section: Methodsmentioning

confidence: 99%

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Akiyoshi

Tanaka

Kiyotani

et al. 2019

British Journal of Surgery

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Background Accumulating evidence suggests that radiotherapy success has an immune‐associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study. Methods CD8+ tumour‐infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole‐exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near‐complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non‐responders. Results Immunohistochemical examinations (275 patients) showed that pre‐CRT CD8+ TIL density was associated with better response to CRT and improved recurrence‐free survival, whereas pre‐CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence‐free survival. Whole‐exome sequencing (74 patients) showed that the numbers of single‐nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non‐responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte‐activation gene 3 (LAG3) (rS = 0·507). Conclusion Pre‐CRT neoantigen‐specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.

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“…11 To fend off tumorigenesis, the immune system includes several layers of active immune cells capable of recognizing altered cells. 12 Natural killer (NK) cells detect the presence or absence of histocompatibility molecules at the surface of cells and are able to integrate these signals to either lyse the target cells, or not. Tumor-associated modified self-antigens can also be presented to T cells, enabling an adaptive immune response to the tumor that consists of helper CD4 T cells and drives the expansion and differentiation of cytotoxic CD8 T cells.…”

Section: Introductionmentioning

confidence: 99%

“…Tumor-associated modified self-antigens can also be presented to T cells, enabling an adaptive immune response to the tumor that consists of helper CD4 T cells and drives the expansion and differentiation of cytotoxic CD8 T cells. 1,12 During this process the tumor microenvironment can influence the quality of the T-cell response and the generation of T CD4 regulatory cells that favor immunologic escape of the tumor.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic analysis of T cells infiltrating colon cancers: Correlations with oncogenetic status

et al. 2015

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Regulatory T Lymphocytes Are Associated with Less Aggressive Histologic Features in Microsatellite-Unstable Colorectal Cancers

Cited by 24 publications

References 39 publications

Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer

Phenotypic analysis of T cells infiltrating colon cancers: Correlations with oncogenetic status

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