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.

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Emerging epidemiological studies report increased cancer occurrence in patients with chronic viral infections, even when such infections are non-oncogenic and not in the same tissue as the cancer. In our recent studies, we observed decreased anti-tumor immune responses in the context of concomitant infection. Specifically, we discovered that anti-melanoma (gp100) CD8+ T cell responses in mice challenged with melanoma are shunted from the tumor site (skin) to the site of influenza infection (lung), leading to faster tumor growth and hastened host death. We observed similar findings with multiple tumor and virus combinations, including patient-derived melanomas in humanized mice infected with HIV. Based on this infection-mediated shunting of anti-tumor CD8+ T cells to the infection site, and towards developing related therapeutic interventions, we sought to determine whether an infection in a particular tissue would improve anti-tumor responses against a tumor also in that same tissue. We discovered that influenza infection within the lungs resulted in 51% fewer tumor foci within the lungs compared to no infection. Tumor foci were further reduced with systemic PD-1 blockade (more than 70% fewer tumor foci compared to no infection or PD-1 blockade alone). Future studies will further dissect the mechanisms underlying these findings in the setting of viral infection. We ultimately aim to translate these findings to combination cancer immunotherapies utilizing viral infections.

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