Inflammatory Monocytes are Potent Antitumor Effectors Controlled by Regulatory CD4+ T cells

“The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4+ T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4+ T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.”


Molecular Pathways: Co-Expression of Immune Checkpoint Molecules: Signaling Pathways and Implications for Cancer Immunotherapy

“The expression of immune checkpoint molecules on T cells represents an important mechanism that the immune system uses to regulate responses to self-proteins. Checkpoint molecules include CTLA-4 (Cytotoxic T Lymphocyte Antigen-4), PD-1 (Programmed Death-1), LAG-3 (Lymphocyte Activation Gene-3), TIM-3 (T cell Immunoglobulin and Mucin protein-3) and several others. Previous studies have identified individual roles for each of these molecules, but more recent data show that co-expression of checkpoint molecules occurs frequently on cancer-specific T cells, as well as on pathogen-specific T cells in chronic infections. While the signaling pathways associated with each checkpoint molecule have not been fully elucidated, blocking multiple checkpoints with specific monoclonal antibodies results in improved outcomes in several chronic viral infections as well as in a wide array of pre-clinical models of cancer. Recent clinical data suggest similar effects in patients with metastatic melanoma. These findings support the concept that individual immune checkpoint molecules may function through non-overlapping molecular mechanisms. Here we review current data regarding immune checkpoint molecule signaling and co-expression, both in cancer and infectious disease, as well as the results of preclinical and clinical manipulations of checkpoint proteins.”


Tumor-Specific T-cell Help Is Associated with Improved Survival in Melanoma

“Despite success with immune checkpoint inhibitors, clinical benefit from cancer vaccines remains elusive. Combined targeting of melanoma-specific CD4+ and CD8+ T-lymphocyte epitopes was associated with improved survival compared with targeting either alone, or when a nonspecific helper epitope was used. We discuss the potential role of antigen-specific CD4 help.”


A Randomized Phase II Trial of Multiepitope Vaccination with Melanoma Peptides for Cytotoxic T Cells and Helper T Cells for Patients with Metastatic Melanoma (E1602)

“Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6MHP) alone (group D), in incomplete Freund’s adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay.”


TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

“Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibro-blasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy.”


TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

“Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibro-blasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy.”


TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

“Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibro-blasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy.”


Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

“Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.”


Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects

“Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.”