Kono, M.; Rokugo, M.; Quadarella, J.; Saito, S.; Komatsuda, H.; Fu, C.; Woo, S.-B. D.; Egloff, A. M.; Uppaluri, R.

Effective T cell immunotherapy requires understanding antigen-specific T cell development during tumorigenesis and immune surveillance. Here, we aimed to examine the dynamics of antigen-specific T cells from tumor initiation through progression in a tobacco carcinogen mimetic, 4-nitroquinoline-1-oxide (4NQO)-induced head and neck carcinogenesis model utilizing genetically engineered K5CreERT/+/ROSAOVA-GFP/p53fl/fl (KOG) mice. Our findings showed that early ovalbumin (OVA) expression via direct lingual tamoxifen (T) did not impact cancer development and survival, by comparing mice with tongue epithelium expressing OVA (KOG/T/OVA+) to those without OVA (KOG/T/OVA-) controlled by doxycycline. This equivalent tumor growth cannot be attributed to the loss of OVA expression. Intriguingly, although OVA-specific T cells were initially generated in tumor-draining lymph nodes (TDLN), they became undetectable 3 weeks after tamoxifen injection. Moreover, therapeutic anti-PD-1 was unable to restore OVA-specific T cells in TDLN and did not yield anti-tumor activity. Remarkably, OVA synthetic long peptide (SLP) vaccine induced OVA-specific T cells in KOG/T/OVA+ mice, and the combination of SLP vaccine and anti-PD-1 significantly reduced tongue tumor burden and prolonged survival. This study highlights the role of impaired endogenous antigen-specific T cell responses in immune resistance in head and neck cancer and the potential of cancer vaccines to improve outcomes.