Cancer immunology research is largely focused on the role of cytotoxic immune responses against advanced cancers. Herein, we demonstrate that CD4+ T helper (Th2) cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells. Th2 cell immunity, stimulated by thymic stromal lymphopoietin, caused the epigenetic reprogramming of the tumor cells, activating mammary gland differentiation and suppressing epithelial–mesenchymal transition. Th2 polarization was required for this tumor antigen–specific immunity, which persisted in the absence of CD8+ T and B cells. Th2 cells directly blocked breast carcinogenesis by secreting IL-3, IL-5, and GM-CSF, which signaled to their common receptor expressed on breast tumor cells. Importantly, Th2 cell immunity permanently reverted high-grade breast tumors into low-grade, fibrocystic-like structures. Our findings reveal a critical role for CD4+ Th2 cells in immunity against breast cancer, which is mediated by terminal differentiation as a distinct effector mechanism for cancer immunoprevention and therapy.

Orsay virus is the only known natural virus pathogen of Caenorhabditis elegans , which shares many evolutionarily conserved pathways with humans. We leveraged the powerful genetic tractability of C. elegans to characterize a novel interaction between zinc, lipids, and virus infection.

Lung cancer is the leading cause of cancer deaths in the United States and across the world. Immunotherapies, which activate tumor-infiltrating cytotoxic T lymphocytes, have demonstrated efficacy for the treatment of advanced-stage lung cancer. However, the potential for harnessing the immune system against the early stages of lung carcinogenesis to prevent cancer development and recurrence remains unexplored. Using a mouse model of lung adenocarcinoma, we investigated the effects of thymic stromal lymphopoietin (TSLP) induction on early cancer development in the lungs. Herein, we demonstrate that systemic TSLP induction suppressed spontaneous lung cancer development in Kras^G12D mice. TSLP drove a significant CD4⁺ T cell response to block lung cancer progression from atypical alveolar hyperplasia to adenocarcinoma. Our findings suggest that TSLP can be used in the early stages of lung cancer development to trigger a lasting immunity in the tissue and prevent the development of advanced disease.

Commensal human papillomaviruses (HPVs) are responsible for persistent asymptomatic infection in the human population by maintaining low levels of the episomal genome in the stratified epithelia. Herein, we examined the immunogenicity of cutaneotropic HPVs that are commonly found in the skin. Using an in silico platform to determine human leukocyte antigen (HLA)–peptide complex binding affinity, we observed that early genes of cutaneotropic HPV types within the same species can generate multiple conserved, homologous peptides that bind with high affinity to HLA class I alleles. Interestingly, we discovered that commensal β, γ, μ, and ν HPVs contain significantly more immunogenic peptides compared with α-HPVs, which include high-risk, oncogenic HPV types. Our findings indicate that commensal HPV proteins have evolved to generate peptides that better complement their host’s HLA repertoire. Promoting higher control by host T cell immunity in this way could be a mechanism by which HPVs achieve widespread asymptomatic colonization in humans. This work supports the role of commensal HPVs as immunogenic targets within epithelial cells, which may contribute to the immune regulation of the skin and mucosa.