Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage

Glaire, Mark A.; Domingo, Enric; Sveen, Anita; Bruun, Jarle; Nesbakken, Arild; Nicholson, George; Novelli, Marco; Lawson, Kay; Oukrif, Dahmane; Kildal, Wanja; Danielsen, Håvard E.; Kerr, Rachel; Kerr, David; Tomlinson, Ian; Church, David N.

doi:10.1038/s41416-019-0540-4

Cited by 42 publications

(34 citation statements)

References 34 publications

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“…Thus, multivariate analysis was conducted following the adjustment of these factors (i.e., mutations of BRCA1/2, POLE and TP53), and the association of low-risk subtype with higher TMB remained statistically significant. Several studies have revealed that TILs play crucial roles in the tumor-immune microenvironment, immune response and prognosis of CRC (44)(45)(46)(47). In the present study, results from the CIBERSORT algorithm showed that the low-risk CRC subtype harbored a significantly higher TIL proportion compared with the high-risk group in TCGA and independent validation cohorts.…”

Section: Discussionsupporting

confidence: 51%

Analysis of immune‑related signatures of colorectal cancer identifying two different immune phenotypes: Evidence for immune checkpoint inhibitor therapy

et al. 2020

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Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of numerous types of cancer, including colorectal cancer (CRC). Patients with CRC and deficient mismatch repair or high microsatellite instability could benefit from ICI treatment, although the response rate of most patients is low. Therefore, the immune subtyping of patients with CRC is required in order to determine the subtypes suitable for ICI treatment. The present study used a cohort of patients with CRC from The Cancer Genome Atlas (TCGA) to perform molecular subtyping, with results validated in three CRC cohorts from the Gene Expression Omnibus. Non-negative matrix factorization was used to achieve consensus molecular subtyping. The tumor immune dysfunction and exclusion algorithm was used to predict potential ICI therapy responses and gene set enrichment analysis was performed to define different pathways associated with the immune response. Two distinct subtypes of CRC were finally identified in TCGA cohorts, which were characterized as significantly different prognostic subtypes (low-risk and high-risk subtypes). Higher expression of programmed death-ligand 1, higher proportion of tumor-infiltrating lymphocytes and tumor mutation burden were significantly enriched in the low-risk subtype. Further pathway analysis revealed that the low-risk subtype was associated with immune response activation and signaling pathways involved in 'antigen processing and presentation'. Three independent CRC cohorts were used to validate the above findings. In summary, two clinical CRC subtypes were identified, which are characterized by significantly different survival outcomes and immune infiltration patterns. The findings of the present study suggest that ICI treatment may be more effective in the low-risk CRC subtype.

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Section: Discussionsupporting

confidence: 51%

Analysis of immune‑related signatures of colorectal cancer identifying two different immune phenotypes: Evidence for immune checkpoint inhibitor therapy

et al. 2020

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“…All the more because the HGP and the immune infiltrate at the TME were found to be independent of clinical risk. Not only has increased infiltration of CD8+ cytotoxic T cells been linked to prognosis in primary CRC 44 and metastatic CRC patients 24 , 40 , 45 but Katz and colleagues have also specifically correlated increased CD8+ T cell infiltration to prolonged survival following resection of CRLM. 21 Brunner et al also found that high CD8+ infiltration was linked to favourable prognosis in patients with CRLM.…”

Section: Discussionmentioning

confidence: 99%

Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis

et al. 2020

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BACKGROUND: Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. METHODS: The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry. RESULTS: One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio. CONCLUSION: The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival.

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“…Transfer of GCSFR −/− CD4 + and CD8 + cells yielded similar effects in reducing MC38 tumor growth when injected in Rag2 −/− mice. CD8 + T cells are present in different stages of CRC, with high levels of cytotoxic T cell infiltration suggesting an anti-tumor immunity (45). Intratumoral CD8 + cell infiltration may act to suppress the micrometastasis of cancer cells into other tissues (46).…”

Section: Discussionmentioning

confidence: 99%

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

et al. 2020

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Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4 + and CD8 + T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR −/− mice, or Rag2 −/− mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for in vitro T cell phenotype analysis. Adoptive transfer of WT or G-CSFR −/− CD4 + of CD8 + T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR −/− mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both in vitro and in vivo approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4 + and CD8 + T cells, whereas G-CSFR −/− T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.

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Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage

Cited by 42 publications

References 34 publications

Analysis of immune‑related signatures of colorectal cancer identifying two different immune phenotypes: Evidence for immune checkpoint inhibitor therapy

Analysis of immune‑related signatures of colorectal cancer identifying two different immune phenotypes: Evidence for immune checkpoint inhibitor therapy

Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

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