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

Abstract

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.

Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma

“…The higher level of FCERG and the MHC class II antigens, HB2B and HB2D, in the F4-T2 tumor suggests a more important immunoreactivity [ 74 ], corroborated by a higher mean Ifng expression and a higher immune cells infiltration in the tumor stroma on histoslides. The higher mean expression level of Cxcl10 relative to that of Ccl2 or Ccl7 in the F4-T2 tumor in comparison with F5-T1 agrees with our analyses of the number of CD8+ versus ED1+ cells infiltrated in the two tumors, and with previous reports that Cxcl10 expression in the TME is associated with a higher level of T-cell infiltration [ 75 ]. Finally, the more substantial increase in Ccl11 expression in F4-T2 than in F5-T1, compared with M5-T1, could also reflect a greater recruitment of leukocytes, in agreement with findings by Wågsäker et al [ 76 ].…”

Chemokine Receptors and Exercise to Tackle the Inadequacy of T Cell Homing to the Tumor Site

“…Melanoma biopsies are segregated into two major subsets such as those infiltrated by T cells and those lacking T cell infiltration-tumors with a T cell-infiltrated phenotype differentially expressed chemokines CCL2, CCL3, CCL4, CCL5, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13 whereas all tumors irrespective of the T cell infiltration level expressed detectable levels of CXCL8/IL-8 and CXCL12/SDF-1 [ 11 ]. By screening a panel of MM cell lines in vitro , Harlin and colleagues found that the majority secreted only a restricted set of chemokines in vitro including predominantly CXCL8/IL-8 and CXCL1/Gro-α [ 11 ], which are in line with studies by us and others [ 3 , 11 , 68 , 69 , 70 , 71 ]…”

IFN-γ: A cytokine at the right time, is in the right place

“…This differential regulation of receptor subunits is thought to influence the balance between the mitogenic and growth inhibitory effects of IFN-γ [41]. Numerous antitumor effects of IFN-γ have been described, and include the regulation of antigen presentation, promotion of inflammatory and chemotactic signals [42,43], activation and polarization of responding leukocytes, as well as direct antiproliferative [44][45][46] and anti-angiogenic effects [47] (Fig. 1).…”