Intranodal injection of PD1 antibody enhances memory T cell responses to improve the efficacy of neoantigen vaccines.

Cold tumors are resistant to neoantigen vaccines (NeoVac) combined with systemic anti-PD1 (aPD1) due to unalleviated T-cell exhaustion in tumor. Here, we found the exhaustion of T cells in tumor-draining lymph nodes (TdLNs) contributed greatly to the exhaustion of T cells in tumor, which could not be improved by systemic aPD1. Therefore, we developed a novel strategy for cold tumors: NeoVac combined with intranodal aPD1 injection (NeoVac + aPD1-i.n). This approach effectively impedes T cell exhaustion in TdLNs and promotes naive T-cell differentiation into central memory T cells (TCM), which further develop into non-exhausted, tumor-specific effector memory T cells (TEM) upon neoantigen stimulation to efficiently kill tumor cells. In CT26 colon cancer and B16F10 melanoma models, NeoVac + aPD1-i.n significantly reduced intratumoral PD1+ T-cell proportions, achieving tumor growth inhibition rates of 70.7% (CT26) and 94.3% (B16F10), with prolonged survival and no obvious adverse effects. By inducing tumor-specific immune response, aPD1-i.n overcomes the drug resistance of NeoVac in cold tumors, holding great clinical translation potential.