ABSTRACT
Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.
Subject(s)
Antibodies, Neutralizing/pharmacology , Immunotherapy/methods , Interleukin-4/antagonists & inhibitors , Neoplasms, Experimental/therapy , Tumor Microenvironment/drug effects , Animals , Antibodies, Neutralizing/immunology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Macrophages/classification , Macrophages/drug effects , Macrophages/immunology , Mice, Inbred BALB C , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Oligodeoxyribonucleotides/immunology , Oligodeoxyribonucleotides/pharmacology , Receptors, OX40/antagonists & inhibitors , Receptors, OX40/immunology , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Time Factors , Treatment Outcome , Tumor Burden/drug effects , Tumor Burden/genetics , Tumor Burden/immunology , Tumor Microenvironment/immunologyABSTRACT
Immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL4 in particular is upregulated. Here, we demonstrate that T follicular helper (Tfh) cells arise in tumor-draining lymph nodes where they produce an abundance of IL4. Deletion of IL4-expressing Tfh cells improves antitumor immunity, delays tumor growth, and reduces the generation of immunosuppressive myeloid cells in the lymph nodes. These findings suggest that IL4 from Tfh cells affects antitumor immunity and constitutes an attractive therapeutic target to reduce immunosuppression in the tumor microenvironment, and thus enhance the efficacy of cancer immunotherapy. Cancer Immunol Res; 5(1); 61-71. ©2016 AACR.
