Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma

Erdag, Gulsun; Schaefer, Jochen T.; Smolkin, Mark E.; Deacon, Donna H.; Shea, Sofia M.; Dengel, Lynn T.; Patterson, James W.; Slingluff, Craig L.

doi:10.1158/0008-5472.can-11-3218

Cited by 490 publications

(494 citation statements)

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“…These data are in line with other observations, stating that the presence of tertiary lymphoid organogenesis (TLO), high endothelial venules (HEV) or germinal centers (GC) residing around the tumor nests are associated with good prognosis in breast carcinoma, non-small cell lung cancer and melanoma. [39][40][41][42] Although some particular chemotherapy regimens elicit a therapy-relevant T cell immunity, they fail to ignite protective B-cell responses, at least in mouse sarcomas and human breast cancers, which however, have been investigated at a relatively early time points. Further in-depth investigation should address antitumor serum reactivities in clinical cases, where TLO or HEV or GC are observed post chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

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Section: Discussionmentioning

confidence: 99%

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

et al. 2013

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“…We have previously reported patient characteristics, the nature of the immune cell infiltrates in these specimens, and their association with patient survival. 9 The observation time was the interval from date of surgery to date of last contact (death or last follow-up). For survival analysis, subjects alive at the time of last follow-up were censored observations at that time.…”

Section: Patients and Databasementioning

confidence: 99%

“…45 Immunohistochemistry Formalin-fixed paraffin-embedded (FFPE) tissue blocks were retrieved from the archives of the Department of Pathology, University of Virginia Health System. TMAs were constructed, as previously reported, 9 with quadruplicate or triplicate 1.0 mm diameter tissue cores were taken from each specimen.…”

Section: Patients and Databasementioning

confidence: 99%

“…We were able to discern and to discriminate hematoxylin counterstained lymphocytes morphologically, and did not require additional immunostains to determine their identity. Counts of CD45 C , CD3 C , CD20 C , CD138 C , CD163 C , CD56 C , FoxP3 C , DC-LAMP C , CD4 C , CD8 C and PD-1 C cells were accessed from the previous report 9 and were reported per mm 2 . Images were obtained using an Olympus BX51 microscope coupled to an Olympus BP70 digital camera (Olympus America Inc., Center Valley, PA), and software Image ProPlus 4.5 for Windows.…”

Section: Quantification Of Pd-l1 Pd-l2 Pd-1 and Tilsmentioning

confidence: 99%

“…[5][6][7][8] Expression of PD-1 is induced on T cells shortly after TCR stimulation, and increased numbers of tumor infiltrating PD-1 C lymphocytes have been associated with prolonged survival of patients with metastatic melanoma. 9 However, ligation of PD-1 can induce programmed cell death in lymphocytes. 7,10,11 or it may induce downregulation of T-cell function.…”

Section: Introductionmentioning

confidence: 99%

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PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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BRAF inhibition curtails IFN‐gamma‐inducible PD‐L1 expression and upregulates the immunoregulatory protein galectin‐1 in melanoma cells

Górniak

Wasylecka-Juszczyńska

Ługowska

et al. 2020

Molecular Oncology

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Although melanoma is considered one of the most immunogenic malignancies, spontaneous T‐cell responses to melanoma antigens are ineffective due to tumor cell‐intrinsic or microenvironment‐driven immune evasion mechanisms. For example, oncogenic BRAF V600E mutation in melanoma cells fosters tumor immune escape by modulating cell immunogenicity and microenvironment composition. BRAF inhibition has been shown to increase melanoma cell immunogenicity, but these effects are transient and long‐term responses are uncommon. For these reasons, we aimed to further characterize the role of BRAF‐V600E mutation in the modulation of PD‐L1, a known immunoregulatory molecule, and galectin‐1 (Gal‐1), a potent immunoregulatory lectin involved in melanoma immune privilege. We report herein that vemurafenib downregulates IFN‐γ‐induced PD‐L1 expression by interfering with STAT1 activity and by decreasing PD‐L1 protein translation. Surprisingly, melanoma cells exposed to vemurafenib expressed higher levels of Gal‐1. In coculture experiments, A375 melanoma cells pretreated with vemurafenib induced apoptosis of interacting Jurkat T cells, whereas genetic inhibition of Gal‐1 in these cells restored the viability of cocultured T lymphocytes, indicating that Gal‐1 contributes to tumor immune escape. Importantly, Gal‐1 plasma concentration increased in patients progressing on BRAF/MEK inhibitor treatment, but remained stable in responding patients. Taken together, these results suggest a two‐faceted nature of BRAF inhibition‐associated immunomodulatory effects: an early immunostimulatory activity, mediated at least in part by decreased PD‐L1 expression, and a delayed immunosuppressive effect associated with Gal‐1 induction. Importantly, our observations suggest that Gal‐1 might be utilized as a potential biomarker and a putative therapeutic target in melanoma patients.

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Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma

Cited by 490 publications

References 45 publications

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

BRAF inhibition curtails IFN‐gamma‐inducible PD‐L1 expression and upregulates the immunoregulatory protein galectin‐1 in melanoma cells

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