Working from human correlates, Newman et al. demonstrated that intratumoral administration of the seasonal flu vaccine reduced tumor growth in mice with B16 melanoma and in NSG mice with patient-derived lung or melanoma xenografts and autologous T cells. The vaccine synergized with PD-L1 blockade even in ICB-resistant tumors. The vaccine increased intratumoral cross-presenting CD8+ DCs, CD8+ T cells, and tumor-specific CD8+ T cells, thus converting the TME from “cold” to “hot”. The antitumor effect was systemic, was dependent on CD8+ T cells, and was not observed with squalene-adjuvanted vaccine nor with intramuscular administration.
Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8(+) T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.