Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer

Pagès, Franck; Berger, Anne; Camus, Matthieu; Sánchez‐Cabo, Fátima; Costes, Anne; Molidor, Robert; Mlecnik, Bernhard; Kirilovsky, Amos; Nilsson, Madeleine; Damotte, Diane; Méatchi, Tchao; Bruneval, Patrick; Cugnenc, Paul-Henri; Trajanoski, Zlatko; Fridman, Wolf‐Herman; Galon, Jérôme

doi:10.1056/nejmoa051424

Cited by 1,839 publications

(1,417 citation statements)

References 29 publications

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“…Additionally, the cytokines and chemokines released by IMCgp100 redirected T cells are strong attractants of a multitude of other immune cells. The density of tumour‐infiltrating lymphocytes has been shown to be predictive of patient survival for a number of different tumours 37, 38, 39, 40…”

Section: Discussionmentioning

confidence: 99%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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SummaryThe success of immune system‐based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti‐CD3 scFv antibody) were previously shown to redirect CD8+ and CD4+ T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma‐specific protein, gp100, presented by HLA‐A*0201) efficiently redirects and activates effector and memory cells from both CD8+ and CD4+ repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8+ T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4+ effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8+ and CD4+ repertoires secrete key pro‐inflammatory cytokines (tumour necrosis factor‐α, interferon‐γ, interleukin‐6) and chemokines (macrophage inflammatory protein‐1α‐β, interferon‐γ‐inducible protein‐10, monocyte chemoattractant protein‐1). At an individual cell level, IMCgp100‐redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti‐cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8+ T cell‐mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma.

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Section: Discussionmentioning

confidence: 99%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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“…Epidermal growth factor receptor was detected on sequential sections using the Invitrogen immunodetection kit (mouse anti-EGFR clone 31G7), as indicated by the manufacturer. After staining, slides were analysed with an image-analysis workstation (Spot Browser version 7; Alphelys), as previously described (Pages et al, 2005). Signal intensity of digitised images was determined using the Spot Browser software; grey values (0 ¼ black to 255 ¼ white) ranged between 102 and 142, and a value inferior or equal to 120 was defined as overexpression.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

et al. 2008

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Cortactin is an actin-binding Src substrate involved in cell motility and invasion. In this study, we sought to examine the prognostic importance of cortactin protein expression in head and neck squamous cell carcinoma (HNSCC). To do so, cortactin and EGF receptor (EGFR) expression was retrospectively evaluated by immunohistochemistry in a tissue microarray composed of 176 HNSCCs with a mean follow-up time of 5 years. Cortactin immunoreactivity was weak to absent in normal epithelial tissue. Overexpression of the protein in 77 out of 176 tumours (44%) was associated with more advanced tumour-node-metastasis stage and higher histologic grade. Cortactin overexpression was associated with significantly increased local recurrence rates (49 vs 28% for high and low expressing carcinomas, respectively), decreased disease-free survival (17 vs 61%), and decreased the 5-year overall survival of (21 vs 58%), independently of the EGFR status. In multivariate analysis, cortactin expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival. Importantly, we identified a subset of patients with cortactin-overexpressing tumours that displayed low EGFR levels and a survival rate that equalled that of patients with tumoral overexpression of both EGFR and cortactin. These findings identify cortactin as a relevant prognostic marker and may have implications for targeted therapies in patients with HNSCC.

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“…Accumulating evidence suggests that tumor progression is governed not only by genetic changes intrinsic to cancer cells but also by epigenetic and environmental factors [10]. Previous studies have suggested that immune infiltrates in CRC may be of clinical importance.…”

Section: Introductionmentioning

confidence: 99%

“…Cancer immunoediting is the ability of the immune system to control and shape cancer, and is the result of three phases, eliminationequilibrium-escape, that function either independently or in sequence [12]. While experimental evidence supports the idea that the innate immune system can promote tumor development through inflammation-dependent mechanisms, infiltration of the tumor by lymphocytes of the adaptive immune system may be a favorable prognostic sign [10]. However, the role of the adaptive immune reaction is still a matter of debate.…”

Section: Introductionmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer

Abstract: Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival.

Cited by 1,839 publications

References 29 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

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Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer

Abstract: Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival.

Cited by 1,839 publications

References 29 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

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Product

Resources

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Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells