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Transcriptional expression of CXCR3 and CCR5 cognate chemokines correlate with CD8+ T-cell infiltration and prolonged survival in colorectal cancer (CRC). These findings were derived mainly from paraffin embedded tissues; thus little is known about the secretion pattern of CD8+ T-cell targeting chemokines from CRCs. Therefore, we developed and introduced a novel platform that assesses the immune mediators that are secreted from live excised tissues. Transcriptional profiling and unsupervised hierarchical clustering of 43 CRCs based on expression of genes that represent the adaptive immune response were used to predict tumors that are strong secretors of T-cell targeting chemokines. Secretion of these mediators were corroborated using flow cytometric analysis of T-cell lineage markers: CD4, CD8, IFN-γ, and GzmB. We demonstrate that stronger secretion of CXCL10 (CXCR3 ligand) and CCL5 (CCR5 ligand) and infiltration of GzmB+CD8+ cytotoxic T-lymphocytes (CTLs) and IFN-γ+CD4+ helper T-cells can be predicted by transcriptional profiling, and that CRCs with stronger T-cell immunity were proportionally skewed towards early TNM stages and lacked distant organ metastasis. Our study represents the first functional analysis of secreted immune mediators from CRCs beyond immunohistochemistry and real-time PCR, and observed active physiological interactions between the tumor cells and the immune cells in the tumor microenvironment.

The purpose of this work was the assessment of cytotoxic reaction mediators - granzymes A and B in the serum of women with ovarian tumors. The study included 120 women with proven ovarian tumors. The control group consisted of 60 healthy women in whom no pathological changes within the reproductive system were detected. Concentrations of granzymes A and B were measured by enzyme-linked immunosorbent (ELISA) assay. The highest concentrations of the studied parameters were observed in serum of women with ovarian cancer. Moreover, the concentrations of granzymes A and B in patients with ovarian cancer were substantially increased in comparison to concentrations in patients with ovarian cystadenomas (P < 0.0001) or ovarian teratomas (P < 0.0001)., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies., (©2013 AACR.)

Background: Sentinel Lymph Node (SLN) status is strongly related to clinical outcome in melanoma patients. In this study we investigated the possible association between the presence of activated and/or suppressive Tumour Infiltrating Lymphocytes (TILs) and SLN status in clinically stage I/II melanoma patients., Methods: Diagnostic primary melanoma samples from 20 patients with a sentinel lymph node metastasis were compared to melanoma samples from 20 patients with a negative sentinel lymph node, who were matched for gender, age and Breslow thickness. Presence of activated Granzyme B positive (GrB+) TILs, presence of suppressive (FoxP3+) TILs and MHC class I antigen expression on tumour cells were analysed by immunohistochemistry., Results: FoxP3 and MHC-I expression had no direct bearing on the presence of melanoma metastases in the SLN. Whereas the presence of activated GrB+ TILs in the primary melanoma had no predictive value for SLN status either, their absence was strongly associated with the presence of metastasis in the SLN (p=0.001). While both GrB+ and FoxP3+ TILs could be detected in SLN metastases, a majority did not display MHC-I expression., Conclusion: These data support a role for cytotoxic T cells in the prevention of early metastasis of melanoma to the draining lymph nodes.