Different Immunologic Microenvironments in Halo Nevi and Melanomas

1
Different Immunologic Microenvironments in Halo
Nevi and Melanomas

• W Liu1,2, P Yu1, M Tretiakova1, T Mentzel3, S
  Hui1, CR Shea2, V Rosic2, Y-X Fu1, T Krausz1
  1Departments of Pathology and 2Dermatology,
  University of Chicago 3Dermatopathologische,
  Gemeinschaftspraxis, Friedrichshafen, Germany

2
Medullary Carcinoma of Breast
Nasopharyngeal Carcinoma (undifferentiated or
lymphoepithelioma)
3
Microsatellite Instability (MSI) of Colon
Carcinoma
Seminoma
4
Keratoacanthoma
5
Halo Nevus
Malignant melanoma
6
Introduction
Tumor cells can be antigenic and immune
recognition of neoplastic cells occurs
Spontaneous tumor regression is often
associated with increased CD8 T cells,
especially activated CD8 T cells
7
Introduction
The CD4 CD25 T cell subset has been
established to be a negative regulator of CD8 T
cell responses
Foxp3 is a transcription factor critical for
CD4CD25 suppressive/regulatory T cell
differentiation and functions
8
Introduction
Foxp3 is a specific marker for CD4 CD25 T cells
Foxp3 T cells suppress antitumor immune
responses by inhibiting CD8 effector functions
Are there any phenotypic differences of tumor
infiltrating lymphocytes in halo nevi and
melanomas with brisk lymphocytic infiltrate?
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Methods
20 halo nevi and 20 melanomas with brisk
lymphocytic infiltrates were analyzed Anti CD4,
CD8, CD25, Foxp3, and perforin antibodies were
utilized to stain consecutive sections T cells
were counted manually
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CD4
Halo Nevus
11
CD8
Halo Nevus
12
CD8
Halo Nevus
CD8
CD4
13
CD8
Peri/intra-tumoral region of halo nevi
14
Peri/intra-tumoral region of halo nevi
15
CD4
Peri/intra-tumoral region of halo nevi
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The Immuno-profile of Lymphocytes in Halo Nevi
CD8/CD4 (2.23)
3
3
2.5
2.5
CD8/CD4 (1.22)
2
2
Foxp3/CD4 (0.67)
Ratio
1.5
1.5
Foxp3/CD4 (0.46)
Perforin/CD8 (0.49)
Perforin/CD8 (0.2)
1
1
0.5
0.5
0
0
Peri/intra-tumoral region of halo nevi
Inter-tumoral region
17
CD8
Regions with brisk lymphocytic infiltrate
Melanomas
18
Regions with brisk lymphocytic infiltrate
Melanomas
19
The Immuno-profile of Lymphocytes in Malignant
Melanoma
3
2.5
2
Ratio
1.5
1
0.5
0
Regions with brisk lymphocytic infiltrate
20
Perforin
Peri/intra-tumoral region of halo nevi
21
Perforin
Regions with brisk lymphocytic infiltrate
of melanomas
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TGFß
TGF-ß controls T cell homeostasis by directly
inhibiting both T cell proliferation and
activation
TGFß is a potent fibrotic factor responsible for
the synthesis of extracellular matrix (ECM) and
is implicated as the major determinant in
pathogenesis of chronic fibroses
24
TGFß
25
Animal Studies
2.5x106 B16-SIY (murine melanoma cell line) were
injected to mice Treatments started (anti-TGFß
300?g/week for 4wks) 11 days after tumor
inoculation
26
4-1BB
Enforced co-stimulation can boost T cell
survival, as well as enhance effector function
of T cells during the priming phase of the
immune response CD137 co-stimulation
substantially enhances CD8 T cell effector
responses Therapeutic use of agonist
anti-CD137 mAbs (4-1BB) has shown to induce
elimination of established tumors
27
Animal Studies
2.5x106 B16-SIY (murine melanoma cell line) were
injected to mice Treatments started
(anti-CD137/4-1BB 300?g/week for 4wks ) 11 days
after tumor inoculation
28
Animal Studies
2.5x106 B16-SIY (murine melanoma cell line) were
injected to mice Treatments started
(anti-TGFß4-1BB/anti-CD137) 11 days after
tumor inoculation
29
Summary (Halo nevi)
Although halo nevi and malignant melanomas share
some clinical features, they have different
phenotypic features of TIL
There is heterogeneity of the immune responses
occurring inside halo nevi
The phenotypic features of TIL may represent the
active anti-tumoral immune responses in
peri/intra-tumoral regions, whereas, the immune
reaction may reflect the post-inflammatory tissue
repair process in inter-tumoral regions
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Summary (Melanomas)
In melanomas, although TIL are also predominantly
CD8 T cells, the majority of these cells do not
express perforin
Melanoma cells might secrete some factors to
inhibit the perforin expression by CD8 T cells
and induce the inactivation of CD8 T cells
Animal model study is needed to address these
issues