Intratumoral CD8⁺ T-cell differentiation is linked to durable HPV-specific immunity after neoadjuvant HPV vaccination with long-acting IL-7 and PD-1 blockade
Year: 2026
Type: preprint
Abstract: Durable antigen-specific immunity is a goal of therapeutic vaccination, but its relationship to intratumoral CD8⁺ T-cell differentiation remains poorly defined. To address this question, we compared anti–PD-1, tirvalimogene teraplasmid (GX-188E), and long-acting IL-7 (GX-I7/NT-I7), alone and in combination, in HPV-positive tumor-bearing mice. Among tested regimens, triple immunotherapy produced the greatest tumor control and a pooled tumor profile enriched for stemness-associated intratumoral CD8⁺ states. We then evaluated the same components in a four-cohort phase 2 neoadjuvant study of 56 patients with resectable HPV-positive head and neck squamous cell carcinoma. In the 11-patient cohort receiving pembrolizumab, GX-188E, and NT-I7, 7 patients had a major pathologic response, including 4 with a pathologic complete response. To define the intratumoral immune program accompanying this activity, paired tumor profiling identified a GZMK⁺ effector-memory CD8⁺ state with cytotoxicity- and memory-associated features. GZMK⁺ effector-memory cells were prominent among T cells bearing clonotypes shared between post-treatment tumors and tumor-draining lymph nodes, consistent with intercompartmental recirculation. Higher tdLN Myc expression in both NT-I7-containing mouse profiles prompted regulatory analysis of the human GZMK⁺ state, revealing treatment-associated higher MYC and lower BATF regulon specificity; in silico IL7R perturbation was consistent with an IL-7-associated reprogramming model. Post-treatment intratumoral MYC-associated and relative MYC/BATF regulon measures were related to HPV16 E6/E7-reactive activation-induced marker responses at 2 years; in eight patients with paired tumors, treatment-associated relative MYC/BATF changes were separately related to a 2-year peptide-responsive CD8⁺ stem cell–like memory phenotype. Together, these findings associate intratumoral GZMK⁺ effector-memory remodeling with HPV-reactive activation and memory phenotypes 2 years later.
Source: Research Square
Authors: Hye Ryun Kim, Chang Gon Kim, Wonrak Son, Yeju Kim, Nam Suk Sim, Dahee Kim, Sun Och Yoon, Chang Geol Lee, Kyung Hwan Kim, Min Hee Hong, Gamin Kim, Jinna Kim, Eui-Cheol Shin, Su-Hyung Park, Jong-Eun Park, Seungeun Lee, Chang Ho Ahn, Jeong Seok Lee, Donghoon Choi, Yoon-Jeong Choi, Yoon Woo Koh, June-Young Koh
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225909565
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