IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy

Berner, Vanessa; Liu, Haiyan; Zhou, Qing; Alderson, Kory L.; Sun, Kai; Weiss, Jonathan M.; Back, Timothy C.; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Li, Renhao; Redelman, Doug; Murphy, William J.

doi:10.1038/nm1554

Cited by 148 publications

(141 citation statements)

References 24 publications

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“…These downstream effects are critical to the development of cellular and humoral immune responses; 16 however, sole CD40 stimulation in murine melanoma vaccine studies has impaired development of durable tumor responses. 17 Our findings with CD86 are similar to others showing diminished expression of this marker in peripheral blood monocytes of patients with melanoma. 18 Diminished expression of CD40 and CD86 has been found in sentinel lymph nodes without metastasis when compared with nonsentinel lymph nodes without metastasis in melanoma 19 and breast cancer.…”

Section: Discussionsupporting

confidence: 91%

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

et al. 2011

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In order to characterize the degree of immunosuppression in regional immunity in patients with melanoma, we used immunohistochemistry to analyze markers of T-cell subtype and polarity, costimulation, dendritic cell maturation, monocytes, lymphatic vasculature, and angiogenesis. Specifically, we analyzed expression of CD4, CD8, CD14, CD40, CD86, CD123, HLA-DR, IL-10, LYVE, VEGFR3, and VEGF-C in lymph nodes. We compared sentinel lymph nodes with and without metastasis from patients with melanoma with both infection inflamed (reactive) and dormant human lymph nodes. There were no differences demonstrated between sentinel lymph nodes with or without metastasis from patients with melanoma in any of the markers that were tested. Both groups of sentinel lymph nodes had fewer CD8 þ T cells than either set of control nodes. Whereas the infection inflamed lymph nodes demonstrated Th2 polarity, the dormant lymph nodes demonstrated Th1 polarity. In conclusion, changes in regional immunity appeared to precede metastasis in melanoma. Whether there was tumor present in sentinel lymph nodes or not, these nodes demonstrated a marked decrease in cytotoxic T cells compared with both sets of controls. Furthermore, the control lymph nodes used for comparison can significantly impact interpretation, as the dormant and reactive lymph nodes markedly varied in their immune profiles. These immunologic changes may explain the successful metastasis of melanoma in the midst of the immune environment of the sentinel lymph node, and lend insights into the mechanisms of lymphatic metastases in other solid malignancies. Modern Pathology (2011) 24, 487-494; doi:10.1038/modpathol.2010.227; published online 10 December 2010Keywords: angiogenesis; cytotoxic T cells; lymph nodes; melanoma; regional immunity Lymph node metastasis is one of the most important prognostic factors in melanoma.1 Whereas patients without nodal involvement generally have excellent outcomes, those with nodal involvement more commonly experience recurrence after resection and diminished survival. Previous investigations suggest that melanoma-draining lymph nodes demonstrate immunologic alterations and are likely immunosuppressed.2 Sentinel lymph nodes are the first lymph nodes to drain a tumor bed, and represent the first expected site of metastasis of melanoma.3,4 Sentinel lymph nodes are a site of contact between tumor-associated antigens and the adaptive immune system and represent a regional unit of metastasis and immune response. Accordingly, sentinel lymph nodes are an ideal setting for the investigations of the early immunologic (endocrine and paracrine) events that lead up to melanoma progression from a primary tumor to metastatic cancer. In the past year, we have described that patients with metastatic melanoma exist in a state of systemic chronic inflammation driven by tumorderived vascular endothelial growth factor (VEGF) overproduction leading to systemic immune polarization to a state of CD4 cell Th2 bias.5 Consequently, we sought to determine if similar differen...

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Section: Discussionsupporting

confidence: 91%

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

et al. 2011

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“…CD4 ϩ T cells are not the only source of IL-2 that provides help for the primary T cell response according to a recent study (49), but for the memory response this remains to be examined. A role for CD27-regulated IFN-␥ production seems less likely, since IFN-␥ was recently shown to impair, rather than enhance, secondary responses of CD8 ϩ T cells (50).…”

Section: Discussionmentioning

confidence: 99%

CD27 Instructs CD4+ T Cells to Provide Help for the Memory CD8+ T Cell Response after Protein Immunization

Xiao

Peperzak

Keller

et al. 2008

The Journal of Immunology

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For optimal quality, memory CD8+ T cells require CD4+ T cell help. We have examined whether CD4+ T cells require CD27 to deliver this help, in a model of intranasal OVA protein immunization. CD27 deficiency reduced the capacity of CD4+ T cells to support Ag-specific CD8+ T cell accumulation at the tissue site after primary and secondary immunization. CD27-dependent CD4+ T cell help for the memory CD8+ T cell response was delivered during priming. It did not detectably affect formation of CD8+ memory T cells, but promoted their secondary expansion. CD27 improved survival of primed CD4+ T cells, but its contribution to the memory CD8+ T cell response relied on altered CD4+ T cell quality rather than quantity. CD27 induced a Th1-diagnostic gene expression profile in CD4+ T cells, which included the membrane molecule MS4A4B. Accordingly, CD27 increased the frequency of IFN-γ- and IL-2-producing CD4+ T cells. It did not affect CD40L expression. Strikingly, MS4A4B was also identified as a unique marker of CD8+ memory T cells that had received CD27-proficient CD4+ T cell help during the primary response. This apparent imprinting effect suggests a role for MS4A4B as a downstream effector in CD27-dependent help for CD8+ T cell memory.

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“…In parallel with this concept, other studies have found that IFN-g enhances activation-induced cell death and that this cytokine might regulate the expansion and persistence of effector T cells (Teff) by enhancing intrinsic and extrinsic pathway-dependent apoptosis [22,23]. Thus, although IFN-g is a crucial effector cytokine in the primary immune response, it can occasionally lead to apoptosis of CD4 1 T cells that are critical for the memory immune response [24]. (Fig.…”

Section: Introductionmentioning

confidence: 91%

IFN‐γ‐STAT1 signal regulates the differentiation of inducible Treg: Potential role for ROS‐mediated apoptosis

et al. 2009

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Regulatory CD41 T cells are important for the homeostasis of immune cells, and their absence correlates with autoimmune disorders. However, how the immune system regulates Treg homeostasis remains unclear. We found that IFN-c-deficient-mice had more forkhead box P3 (FOXP3 1) cells than WT mice in all secondary lymphoid organs except the thymus. However, T-bet-or IL-4Ra-deficient mice did not show a similar increase. In vitro differentiation studies showed that conversion of naïve T cells into FOXP3 1 cells (neo-generated inducible Treg (iTreg)) by TGF-b was significantly inhibited by IFN-c in a STAT-1-dependent manner. Moreover, an in vivo adoptive transfer study showed that inhibition of FOXP3 1 iTreg generation by IFN-c was a T-cell autocrine effect. This inhibitory effect of IFN-c on iTreg generation was significantly abrogated after N-acetyl-L-cysteine treatment both in vitro and in vivo, indicating that IFN-c regulation of iTreg generation is dependent on ROS-mediated apoptosis. Therefore, our results suggest that autocrine IFN-c can negatively regulate the neo-generation of FOXP3 1 iTreg through ROSmediated apoptosis in the periphery.

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IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy

Cited by 148 publications

References 24 publications

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

CD27 Instructs CD4+ T Cells to Provide Help for the Memory CD8+ T Cell Response after Protein Immunization

IFN‐γ‐STAT1 signal regulates the differentiation of inducible Treg: Potential role for ROS‐mediated apoptosis

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