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Immune-escape markers in relation to clinical outcome of advanced melanoma patients following immunotherapy

Significance statement 

Immunotherapy currently represents the most promising therapeutic approach for advanced melanoma patients with potentially life-saving treatments.  Despite improved immunotherapeutic regimens to melanoma, significant numbers of patients with advanced melanoma still respond poorly or show relapses. Many immune regulating factors and cell types play a decisive role in the potency of the anti-tumor immune response. Immune-(escape)-mechanisms are found in tumors, while their influence on the efficacy of anti-tumor immunity is still not well defined. In this study, we investigated a large series of immune (escape) markers, relevant to T-cell function, as potential biomarkers for clinical outcome following immunotherapy. We retrospectively studied the expression of immune (escape) markers in metastatic melanoma tissues of 27 patients prior to autologous tumor-cell-vaccination and 16 patients who were intended to treat but after all not vaccinated due to rapid disease progression. Immunohistochemical data of infiltrating (suppressive) cells, such as T-cells, regulatory T-cells (Treg), myeloid-derived-suppressor cells (MDSC) and mast cells, or the expression of T-cell inhibitory factors (PD-1/PDL-1, IDO, galectins), cytotoxic molecules (granzyme-B), melanocyte-differentiation-antigens, HLA class-I and tolerogenic cytokines (IL-1, IL-6, IL-10, TNFa, TGFb) were correlated statistically to clinical outcome and overall survival (OS). Significantly more tumor-infiltrating CD4+ and CD8+ T-cells (both P<0.05) were found in non-progressors to vaccination (n=9;median OS=56 months), compared to progressors (n=18;median OS=9.5 months). Moreover, granzyme-B expression was elevated in the tumor of non-progressors, suggesting activated cytotoxic T or natural killer cells. T-cell infiltration and granzyme-B expression significantly correlated with overall OS. T-cell inhibitory factors and suppressive cells did not correlate with OS, suggesting minor influence of these immune escape markers on clinical outcome. The data of progressors were comparable to patients with rapid progression (not vaccinated)(n=16;median OS=3 months). Our study showed that tumor tissue with high numbers of activated CD4+ and CD8+ T-cells manifested in prolonged PFS and/or OS in patients receiving autologous tumor cell vaccination, emphasizing the therapeutic relevance of tumor-infiltrating T-cells for clinical outcome. Patients with low T-cell presence in the tumor tissue may require additional inventions to increase T-cell infiltration in the tumor, e.g. by combining immune checkpoint blockade with vaccination or adoptive T-cell transfer. Our study further indicates that analysis of tumor tissue characteristics prior immunotherapy may therefore be a valuable tool to select patients with potential clinical benefit.

Figure Legend: biopsies of patients showed that tumors at baseline with high numbers of activated T-cells manifested in favorable prognosis in patients receiving autologous tumor cell vaccination. This indicates a more prominent role for T-cell infiltration and activation in the tumor tissue for clinical outcome than immune-escape mechanisms. Therefore, analysis of tumor tissue characteristics before immunotherapy can be useful to optimally select patients, who will have increased chances of a favorable clinical outcome from the immunotherapy or to offer patients with low T-cell presence in the tumor tissue additional inventions to increase T-cell infiltration in the tumor (e.g. by combining immune checkpoint blockade with vaccination or adoptive T-cell transfer).

 

Immune-Escape Markers in Relation to Clinical Outcome of Advanced Melanoma Patients Following Immunotherapy

 

 

 

 

 

 

 

 

 

 

Journal Reference

Tjin EP1,  Krebbers G1, Meijlink KJ1, van de Kasteele W4, Rosenberg EH3, Sanders J2, Nederlof PM3, van de Wiel BA2, Haanen JB4,5, Melief CJ6, Vyth-Dreese FA4, and Luiten RM1.

Cancer Immunol Res. 2014 ;2(6):538-46.

1Department of Dermatology, Academic Medical Center, University of Amsterdam;

2Department of Pathology; 3Molecular Diagnostic Laboratory; 4Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; 5Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and

6ISA Pharmaceuticals, Leiden, the Netherlands

Abstract

In this study, we investigated a large series of immune (escape) markers, relevant to T-cell function, as potential biomarkers for clinical outcome following  immunotherapy.  We retrospectively studied the expression of immune (escape) markers in metastatic melanoma tissues of 27 patients before autologous tumor cell vaccination, and 16 patients who were intended to treat but were not vaccinated because of rapid disease progression. Immunohistochemical data of infiltrating (suppressive) cells, such as T cells, regulatory T cells, myeloid-derived suppressor cells, and mast cells, or the expression of T-cell inhibitory factors (PD-1/PD-L1, IDO, and galectins), cytotoxic molecules (granzyme-B), melanocyte differentiation antigens, HLA class-I and tolerogenic cytokines [interleukin (IL)-1, IL-6, IL-10, TNF-{Alpha}, and TGF-{Beta}] were correlated statistically to clinical outcome and overall survival (OS). Significantly more tumor-infiltrating CD4(+) and CD8(+) T cells (both P < 0.05) were found in nonprogressors to vaccination (n = 9; median OS, 56 months), compared with progressors (n = 18; median OS, 9.5 months). Moreover, granzyme-B expression was elevated in the tumors of nonprogressors, suggesting activated cytotoxic T cells or natural killer cells. T-cell infiltration and granzyme-B expression significantly correlated with overall OS. T-cell inhibitory factors and suppressive cells did not correlate with OS, suggesting minor influence of these immune-escape markers on clinical outcome. The data of progressors were comparable with those from patients with rapid progression (not vaccinated; n = 16; median OS, 3 months). Our study shows that high numbers of intratumoral activated CD4(+) or CD8(+) T cells, before autologous tumor cell vaccination, are associated with favorable clinical outcome. Analyses of these markers in the patients’ tumor tissues before immunotherapy may therefore be a valuable tool to select patients for whom the treatment may result in potential clinical benefit.

©2014 American Association for Cancer Research.

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