Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment

By H. Harlin, Yuru Meng, A. Peterson, Y. Zha, M. Tretiakova, C. Slingluff, M. McKee, T. Gajewski. Cancer Research, 2009

1,037 citations recorded by the source corpus.

Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/de6aee854d54470ca98712d9ffc28609124b32d0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. T. Gajewski
2. G. Barber
3. V. Kuchroo
4. S. Spranger
5. Antoni Ribas
6. D. Dai
7. B. Horton
8. Arlene H. Sharpe

In Oncology

1. Antoni Ribas
2. G. Barber
3. T. Gajewski
4. S. Spranger
5. V. Bronte
6. D. Powell
7. George Coukos
8. Arlene H. Sharpe

Citations in the corpus

• Spatially organized multicellular immune hubs in human colorectal cancer (2021, background): “Furthermore, several studies have linked the CXCR3 chemokine system to T cell entry into tissues, including CD8+ T cell recruitment in melanoma (Harlin et al., 2009), viral infection (Nakanishi et al.”
• Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells (2013, methodology): “The T cell–inflamed subset also expresses chemokines for T cell recruitment (13) and a type I interferon (IFN) transcriptional profile that appears to participate in innate immune sensing (19, 20).”
• Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours (2021, background): “These preliminary data showed an inverse association between the change in AXIN2 expression and the change in both a chemokine signature associated with T-cell recruitment (based on CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10) and an activated dendritic cell signature (based on BATF3, ITGAE, IRF8, CCR5, C”
• Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells (2011, background): “Interestingly, in addition to inflammatory and endothelial cells, tumor cells themselves are capable of producing CTL-attracting chemokines (Murphy, 2001; Harlin et al., 2009).”
• Cold Tumors: A Therapeutic Challenge for Immunotherapy (2019, background): “CXCL9 and CXCL10 (CXCL11 in humans) are key chemokines in the recruitment of CD8+ T cells engaging the CXCR3 on their surface and their production is generally deregulated in “non-inflamed” tumors (47).”
• Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “For example, expression of CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10 has been correlated with the presence of TILs in melanoma (Harlin et al., 2009; Spranger et al., 2015).”
• Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment (2019, background): “Hot tumors are characterized by transcripts encoding for various T Frontiers in Immunology | www.frontiersin.org 5 May 2019 | Volume 10 | Article 1078 cell-lineage markers, innate immune cell molecules, chemokines that regulate effector T cell recruitment and also for molecules mediating immune supp”
• An immune-active tumor microenvironment favors clinical response to ipilimumab (2012, background): “In particular, higher expression of CCL4, CCL5, CXCL9, CXCL10, and CXCL11 might be of importance, as their presence in the tumors can promote T cell inWltration, which is a prerequisite for immune-mediated tumor regression [15, 44].”
• Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015, background): “Transcriptional profiling analyses of melanoma patients have revealed that tumors containing infiltrating activated T cells are characterized by a type I IFN transcriptional signature (Harlin et al., 2009).”