Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease

Clancy‐Thompson, Eleanor; Perekslis, Thomas J.; Croteau, Walburga; Alexander, Matthew P.; Chabanet, Tamer B.; Turk, Mary Jo; Huang, Yina H.; Mullins, David W.

doi:10.1158/2326-6066.cir-15-0015

Cited by 36 publications

(43 citation statements)

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“…The role of CXCR3 and the ligands CXCL9 and CXCL10 in anti-tumor immunity is well established (29, 34, 57, 58). In a recent study, Mikuchi et.al elegantly demonstrated that CXCR3 mediated signalling to be a critical and an indispensable checkpoint for tumor antigen specific CD8 + T cells to traffic across the tumor vasculature for carrying out effective tumoricidal activity in mice and human melanoma (29).…”

Section: Discussionmentioning

confidence: 99%

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Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors

Chheda

Sharma

Jala

et al. 2016

The Journal of Immunology

129

108

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Immunotherapies have shown considerable efficacy for the treatment of various cancers, but a multitude of patients remain unresponsive for various reasons, including poor homing of T cells into tumors. In this study, we investigated the roles of the leukotriene B4 receptor, BLT1, and CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, under endogenous as well as vaccine-induced antitumor immune response in a syngeneic murine model of B16 melanoma. Significant accelerations in tumor growth and reduced survival were observed in both BLT1−/− and CXCR3−/− mice as compared with wild-type (WT) mice. Analysis of tumor-infiltrating leukocytes revealed significant reduction of CD8+ T cells in the tumors of BLT1−/− and CXCR3−/− mice as compared with WT tumors, despite their similar frequencies in the periphery. Adoptive transfer of WT but not BLT1−/− or CXCR3−/− CTLs significantly reduced tumor growth in Rag2−/− mice, a function attributed to reduced infiltration of knockout CTLs into tumors. Cotransfer experiments suggested that WT CTLs do not facilitate the infiltration of knockout CTLs to tumors. Anti–programmed cell death-1 (PD-1) treatment reduced the tumor growth rate in WT mice but not in BLT1−/−, CXCR3−/−, or BLT1−/−CXCR3−/− mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti–PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti–PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.

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Section: Discussionmentioning

confidence: 99%

“…Among the immune cells, CD4 + T cells were considered the major producers of CXCL9 as well as IFNγ in the metastatic nodules in lung (34). While most myeloid cells can readily produce LTB 4 , the source of this BLT1 ligand in the B16 tumors remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors

Chheda

Sharma

Jala

et al. 2016

The Journal of Immunology

129

108

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“…IFNγ can induce CXCL9-11 production from human melanoma cells in vitro [11]. These chemokines promote the migration of CXCR3 + T-cells into tumors [11], in murine models, expression of IFNγ in the TME enhances T-cell mediated anti-tumor immunity [25], and CXCR3 + T-cells have been demonstrated to mediate tumor rejection [12,26]. In patients, CXCL10 expression in the TME is associated with better T-cell infiltration, tumor control, and disease-free survival [27–29].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

Mauldin

Wages

Stowman

et al. 2016

Cancer Immunol Immunother

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Introduction Optimal approaches to induce T-cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T-cell recruitment, and may be induced by IFNγ. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11, and will induce T-cell recruitment and anti-tumor immune signatures in melanoma metastases. Patients and Methods Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T-cell responses to vaccination were assessed in PBMC by IFNγ ELIspot assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression and gene expression. Results Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T-cell responses to vaccine were detected in 6 of 9 patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion The melanoma vaccine induced circulating T-cell responses, but they failed to infiltrate metastases, thus highlighting the need for combination strategies to support T-cell infiltration. A single intratumoral injection of IFNγ induced T-cell attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T-cells in melanoma metastases.

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“…Previous studies evaluated expression of individual HR ligands on tumor vasculature, and concluded that the expression of E-selectin (15,25), ICAM-1(15), CXCL9(20,21), and VCAM-1(19) was often low. Expression of VCAM-1 correlates with T-cell representation in several human cancers (16,23,24).…”

Section: Discussionmentioning

confidence: 99%

“…LFA-1/ICAM-1 interactions are common mediators of leukocyte engagement with other cells and, not surprisingly, play an important role in entry into murine melanoma and human glioblastoma (15–17). CXCR3 interactions with CXCL9/10 mediate entry into subcutaneous (SC) and intracranial murine melanomas (18–20) and correlated with the representation of CD8 + T cells in melanomas growing in lungs (21). α 4 β 1 /VCAM-1 interactions are required for CD8 + T-cell accumulation in intracranial melanoma (22) and in SC melanoma following kinase inhibitor-induced VCAM-1 upregulation (19).…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry

Woods

Wilson

Srivinisan

et al. 2017

Cancer Immunology Research

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Although CD8+ T cells are critical for controlling tumors, how they are recruited and home to primary and metastatic lesions is incompletely understood. We characterized the homing receptor (HR) ligands on tumor vasculature to determine what drives their expression and their role in T cell entry. The anatomic location of B16-OVA tumors affected the expression of E-selectin, MadCAM-1, and VCAM-1, whereas the HR ligands CXCL9 and ICAM-1 were expressed on the vasculature regardless of location. VCAM-1 and CXCL9 expression was induced by IFNγ-secreting adaptive immune cells. VCAM-1 and CXCL9/10 enabled CD8+ T-cell effectors expressing α4β1 integrin and CXCR3 to enter both subcutaneous and peritoneal tumors, whereas E-selectin enabled E-selectin ligand+ effectors to enter subcutaneous tumors. However, MadCAM-1 did not mediate α4β7+ effector entry into peritoneal tumors due to an unexpected lack of luminal expression. These data establish the relative importance of certain HRs expressed on activated effectors and certain HR ligands expressed on tumor vasculature in the effective immune control of tumors.

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Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease

Cited by 36 publications

References 36 publications

Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors

Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry

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