Tumor progression despite massive influx of activated CD8+ T cells in a patient with malignant melanoma ascites

Abstract

Although melanoma tumors usually express antigens that can be recognized by T cells, immune-mediated tumor rejection is rare. In many cases this is despite the presence of high frequencies of circulating tumor antigen-specific T cells, suggesting that tumor resistance downstream from T cell priming represents a critical barrier. Analyzing T cells directly from the melanoma tumor microenvironment, as well as the nature of the microenvironment itself, is central for understanding the key downstream mechanisms of tumor escape. In the current report we have studied tumor-associated lymphocytes from a patient with metastatic melanoma and large volume malignant ascites. The ascites fluid showed abundant tumor cells that expressed common melanoma antigens and retained expression of class I MHC and antigen processing machinery. The ascites fluid contained the chemokines CCL10, CCL15, and CCL18 which was associated with a large influx of activated T cells, including CD8(+) T cells recognizing HLA-A2 tetramer complexes with peptides from Melan-A and NA17-A. However, several functional defects of these tumor antigen-specific T cells were seen, including poor production of IFN-gamma in response to peptide-pulsed APC or autologous tumor cells, and lack of expression of perforin. Although these defects were T cell intrinsic, we also observed abundant CD4(+)CD25(+)FoxP3(+) T cells, as well as transcripts for FoxP3, IL-10, PD-L1/B7-H1, and indoleamine-2,3-dioxygenase (IDO). Our observations suggest that, despite recruitment of large numbers of activated CD8(+) T cells into the tumor microenvironment, T cell hyporesponsiveness and additional negative regulatory mechanisms can limit the effector phase of the anti-tumor immune response.

Mechanisms of local immunosuppression in cutaneous melanoma

“…We detected the presence of suppressor/regulatory T lymphocytes and tolerogenic DCs at all stages of melanoma development. FOXp3-positive, IL-10 producing T lymphocytes were recently reported in tumour, blood and ascites from patients with advanced melanoma, and were associated with melanoma-related immunosuppression (Appay et al, 2006;Cesana et al, 2006;Harlin et al, 2006). As well as FOXp3 we have also demonstrated expression of ILT3, a marker of tolerogenic DCs and have correlated markers of local immunosuppression with melanoma progression.…”

“…Indoleamine 2,3-dioxygenase is an enzyme produced mainly by APC of myeloid origin that suppresses T lymphocyte-related antigen-specific immune responses (Mellor and Munn, 2004). It has also been associated with disease progression in various tumour types, including colorectal cancer (Brandacher et al, 2006), haemangioma (Ritter et al, 2003) and melanoma (Harlin et al, 2006).…”

Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication

“…Development of antitumor vaccines often aims at generation of strong antitumor T-cell reactivity (14). Although CTLs are crucial effector cells against cancer, the high frequency of HLA class I antigen down-regulation in malignancies may limit the effectiveness of vaccines aimed at stimulating CTL responses (15,16). In addition, recent studies showed that even a massive influx of activated CD8 + T cells in a patient with malignant melanoma was not sufficient for inhibition of tumor progression (16).…”

Overall survival and PD‐L1 expression in metastasized malignant melanoma

“…Because of its role in tumor development, the prognostic value of PD-L1 has been studied in several instances and found to be associated with poor prognosis in non-small cell lung cancer, gastric carcinoma, and renal cell carcinoma. 25,26,35 Despite several reports of PD-L1 expression in melanoma, [21][22][23]40 its prognostic relevance in melanoma patients has been suggested only recently. 41 In line with this recent study, the current work addressed whether, in the melanoma setting, PD-L1 expression increases during disease progression and whether its expression correlates with other immunological …”