Abstract
Patients with cancer are at elevated risk of life-threatening infections due to immunosuppression caused by both malignancy and its treatments, which compromises pre-existing anti-microbial immune memory established by prior infection or vaccination. Despite this systemic suppression, pathogen-specific memory T (T(MEM)) cells can infiltrate the tumor microenvironment in large numbers as tumor antigen-irrelevant bystander T(MEM) cells. We previously developed an engineered oncolytic virus encoding bystander T(MEM) cell epitopes (OV-BYTE) that redirected tumor-infiltrating bystander T(MEM) cells against tumors to control malignancy progression; however, it remains unknown whether OV-BYTE could concurrently reinforce systemic T(MEM) cell responses and thereby function as a booster vaccination to protect against microbial infection during malignancy. Here, we found that OV-BYTE triggered a robust proliferation burst of pathogen-specific CD4(+) T(MEM) cells in the periphery. These cells exhibited a newly differentiated TCF-1(lo)CD39(hi) phenotype with superior type 1 effector functions and were characterized by substantial granzyme B (GzmB) production. Further lineage-tracing studies revealed their origin from tumor-resident bystander CD4(+) T(MEM) counterparts, with epigenetic modifications preserving their lineage stability and effector functionality. Critically, these GzmB-producing peripheral CD4(+) T(MEM) cells endowed OV-BYTE with augmented anti-infection capacity. Thus, our study introduces a strategy that concurrently tackles malignancy and infectious complications by repurposing pre-existing pathogen-specific bystander T(MEM) cell resources.