Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

Galon, Jérôme; Costes, Anne; Sánchez‐Cabo, Fátima; Kirilovsky, Amos; Mlecnik, Bernhard; Lagorce-Pagès, Christine; Tosolini, Marie; Camus, Matthieu; Berger, Anne; Wind, Philippe; Zinzindohoué, Franck; Bruneval, Patrick; Cugnenc, Paul-Henri; Trajanoski, Zlatko; Fridman, Wolf‐Herman; Pagès, Franck

doi:10.1126/science.1129139

Cited by 5,413 publications

(4,655 citation statements)

References 28 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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“…In contrast, molecular pathology provides a clinically feasible diagnostic toolbox and promises to deliver more accurate prognostics and response prediction. Several biomarkers have shown promise in CRC (Birgisson et al ., 2010; Bruun et al ., 2015; Schetter et al ., 2008), but very few have been validated in large independent datasets, except from the Immunoscore (El Sissy et al ., 2017; Galon et al ., 2006), which is a prognostic tool that quantifies the levels of CD3‐ and CD8‐positive cells in the tumor center and at the invasive margin.…”

Section: Introductionmentioning

confidence: 99%

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

et al. 2018

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We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

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“…To this end, presence of tumor infiltrating lymphocytes (TILs) has been shown to correlate with better prognosis of several solid cancers including MM, 7 colon carcinoma, 8 ovarian cancer 9 and breast cancer. 10 This is supported by accumulating data linking response to immune therapy with a brisk infiltration of T cells in the tumor.…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

et al. 2018

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Adoptive cell therapy (ACT) using in vitro expanded tumor infiltrating T lymphocytes (TILs) from biopsy material represents a highly promising treatment of disseminated cancer. A crucial prerequisite for successful ACT is sufficient recruitment of transferred lymphocytes to the tumor site; however, despite infusion of billions of lymphocytes, T cell infiltration into the tumor post ACT is limited. By PCR and Luminex analyses we found that a majority of malignant melanoma (MM) cell lines expressed chemokines CXCL1/Groα, CXCL8/IL-8, CXCL12/SDF-1 and CCL2. Concerning expression of the corresponding receptors on T cells, only the IL-8 receptor, CXCR2, was not expressed on T cells. CXCR2 was therefore expressed in T cells by lentiviral transduction, and shown to lead to ligand specific transwell migration of engineered T cells, as well as increased migration towards MM conditioned medium. In vivo homing was assessed in a xenograft NOG mouse model. Mice with subcutaneous human melanoma were treated with MAGE-A3 specific T cells transduced with either CXCR2 or MOCK. Transducing T cells carrying the MAGE-A3a3a high affinity T cell receptor with CXCR2 increased tumor infiltration. Flow cytometry analysis 7 days after ACT showed a doubling in CD3+ T cells in tumor digest of mice receiving CXCR2 transduced T cells compared to MOCK treated mice, a finding confirmed by immunohistochemistry. In conclusion, our CXCR2 transduced T cells are functional in vitro and transduction with CXCR2 increases in vivo homing of T cells to tumor site.

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Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

Cited by 5,413 publications

References 28 publications

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

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

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

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Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

Cited by 5,413 publications

References 28 publications

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

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

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

Contact Info

Product

Resources

About

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

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