Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment

Gajewski, Thomas F.

doi:10.1158/1078-0432.ccr-05-2517

Cited by 93 publications

(72 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 Why tumors rich in tumor infiltrating lymphocytes have significant differences in behavior and clinical courses is unknown, although several mechanisms have been suggested in the melanoma immunity. 13 We hypothesized that the functional status of tumor infiltrating lymphocytes are different in different tumors, which might be important in the tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

et al. 2008

View full text Add to dashboard Cite

Tumor infiltrating lymphocytes have been correlated with a better prognosis for some tumors and medullary carcinoma of breast is a good example. However, in a recent study of invasive micropapillary carcinoma of breast, tumor infiltrating lymphocytes were associated with increased lymph node metastasis and a poorer prognosis. To explore possible mechanisms underlying this difference in immune responsiveness and tumor behavior, 28 cases of invasive micropapillary carcinoma with prominent lymphocyte infiltration were compared with 29 cases of medullary carcinoma. In both tumors, the majority of tumor infiltrating lymphocytes were T lymphocytes (Po0.01) with CD8 þ T lymphocytes predominant (Po0.01). Significantly, functional differences in CD8 þ cytotoxic T lymphocytes were identified in the two types of tumor. While lymphocytes infiltrated both the stroma and epithelial components of medullary carcinoma, the tumor infiltrating lymphocytes of invasive micropapillary carcinoma were almost exclusively confined to the stroma. Tumor infiltrating lymphocytes of medullary carcinoma showed stronger expression of FasL than those in invasive micropapillary carcinoma (Po0.01) and medullary carcinoma cells exhibited stronger expression of Fas than invasive micropapillary carcinoma cells did (Po0.01). In the subgroups of tumors with strong ( þ þ / þ þ þ ) Fas expression, double immunohistochemistry revealed that most of the tumor infiltrating lymphocytes in medullary carcinoma, particularly those infiltrating the tumor nests, were CD8 þ cytotoxic T lymphocytes, but not so in invasive micropapillary carcinoma. Furthermore, upregulated expression of perforin, granzyme B and FasL by cytotoxic T lymphocytes was greater in medullary carcinoma than invasive micropapillary carcinoma (Po0.01, respectively). The results suggest that effective immunity provided by tumor infiltrating lymphocytes varies in different tumors and the relative lack of tumor-killing cytotoxic T lymphocytes in invasive micropapillary carcinoma may explain, in part, the adverse association of tumor infiltrating lymphocytes with the biological behavior of invasive micropapillary carcinoma of breast. Modern Pathology (2008Pathology ( ) 21, 1101Pathology ( -1107 doi:10.1038/modpathol.2008 published online 9 May 2008 Keywords: tumor infiltrating lymphocytes; invasive micropapillary carcinoma; medullary carcinoma; breast; laser scanning confocal microscope Local and systemic inflammatory responses play an important role in the progression of a variety of common solid tumors. Tumor infiltrating lymphocytes are believed to represent the local immune response, a key mechanism in controlling tumor growth and metastasis, and an independent prognostic indicator for many tumors.1,2 This is well demonstrated in medullary carcinoma of breast which is characterized by large sheets of poorly differentiated tumor cells and a prominent lymphoplasmacytic infiltrate, rare lymph node metastasis and a good prognosis. 3 Invasive micropapillary carcinoma of breast is composed of sma...

show abstract

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

et al. 2008

View full text Add to dashboard Cite

show abstract

“…It is likely that not all T cells in exudates can be activated by MT110 because they are anergic due to escape mechanisms of the pleural tumor cells, due to Mean values ± standard deviation (SD) and P-values are given (n.s. = not significant) a -MT110 = control, as described in ''Patients and methods '' exposure to tumor cell-derived TGF-b, or expression of PD receptor ligands B7-H1 or B7-H4, or the tryptophan degrading enzyme indole 2,3-dioxygenase (IDO) by cancer cells [45,46]. Because T cell activation by MT110 is dependent on the presence of target cells [25], it is also conceivable that low numbers of EpCAM-expressing cells have limited the polyclonal T cell activation by MT110.…”

Section: Discussionmentioning

confidence: 99%

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Witthauer

Schlereth

Brischwein

et al. 2008

Breast Cancer Res Treat

View full text Add to dashboard Cite

In the present study, the efficacy of a new drug, i.e. the bispecific single-chain antibody MT110 targeting the epithelial antigen EpCAM and the T-cell antigen CD3 was tested ex vivo in malignant pleural effusions (MPEs). EpCAM ? epithelial cells were found in 78% of the MPEs (n = 18). Ex vivo treatment of seven MPEs resulted in a dose-dependent specific lysis of 37 ± 27% (±SD) EpCAM ? cells with 10 ng/ml (P = 0.03) and 57 ± 29.5% EpCAM ? cells with 1,000 ng/ml MT110 (P = 0.016) after 72 h. As a prerequisite for redirected lysis, stimulation of he autologous CD4 ? and CD8 ? cells in MPE by 1,000 ng/ml MT110 resulted in 21 ± 17% CD4 ? /CD25 ? and 29.4 ± 22% CD8 ? /CD25 ? cells (P = 0.016, respectively) after 72 h. This was confirmed by a 22-fold release of TNF-a and 230-fold release of IFN-c (1,000 ng/ml, 48 h, P = 0.03, respectively). Thus, relapsed breast cancer patients resistant to standard treatment might benefit from targeted therapy using MT110.Keywords Malignant pleural effusion Á Breast cancer Á Bispecific antibody Á EpCAM Á CD3 Á MT110 Á Ex vivo therapy

show abstract

“…5 First, a large effort was invested to obtain reliable PD-L1 staining in paraffin-embedded material, because in our hands the antibody that has been claimed to stain best in paraffin, PD-L1, 28,29 gave high background staining. A broad array of commercially available mAbs, as well as mAbs provided by the University of Vienna (Vienna, Austria) and clones provided by Medarex (Princeton, NJ), were tested for their staining patterns.…”

Section: Pd-l1 and Malignant Melanoma/gadiot Et Almentioning

confidence: 99%

Overall survival and PD‐L1 expression in metastasized malignant melanoma

Gadiot

Hooijkaas

Kaiser

et al. 2010

Cancer

214

138

View full text Add to dashboard Cite

BACKGROUND: Cancers are known to elude the immune system, for example, by MHC loss, FAS up-regulation, or increased secretion of TGF-beta. Recently, ligands of coinhibitory receptors like programmed cell death ligand-1 (PD-L1, B7-H1) have come to attention for their role in tumor immune escape. Various tumors have been tested for PD-L1 expression, and conflicting results were obtained regarding its correlative impact on patient survival. This study aimed to determine the prognostic relevance of PD-L1 expression for the survival of melanoma patients. METHODS: Paraffin-embedded nevi, primary melanoma, and in-transit, lymph node, and distant organ metastases from a set of 63 stages III-IV melanoma patients referred to the Netherlands Cancer Institute between 2000 and 2004 for a sentinelnode procedure or systemic therapy were studied. A large effort was invested in validating specific PD-L1 staining. In addition to immunological factors such as T-cell infiltration (CD8, CD4, and regulatory T cells), TGF-beta and MHC-I expression were assessed. RESULTS: Longitudinal analysis revealed no relevant PD-L1 expression on primary melanoma compared with metastatic disease. No significant correlations with prognosis were found regarding immunological factors, whereas known prognostic markers such as Breslow thickness and sex could be confirmed. Analyses of the overall survival of our patient cohort did not reveal a negative association with PD-L1 expression. CONCLUSIONS: Correlation of overall survival with PD-L1 expression by melanoma cells remains controversial, and future clinical studies should focus on antibody validation and time of analysis in respect to disease progression.

show abstract

Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment

Cited by 93 publications

References 24 publications

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Overall survival and PD‐L1 expression in metastasized malignant melanoma

Contact Info

Product

Resources

About