Unbiased chemokine receptor screening reveals similar efficacy of lymph node- and tumor-targeted T cell immunotherapy

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 9; pp. 3111 - 3124
• Main Authors: Pachmayr, Ludwig O., Muehlbauer, Anton, Flommersfeld, Sophie, Graml, Franziska, Hoenninger, Julian, von Baumgarten, Louisa, Buchholz, Veit R., Grassmann, Simon
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2023; Springer Nature B.V
• Subjects: Animals; Brief Report; Cancer Research; CD8 antigen; CD8-Positive T-Lymphocytes; Cell therapy; Chemokine receptors; Chemokines; Cytotoxicity; Homing behavior; Humans; Immunology; Immunoregulation; Immunotherapy; Immunotherapy, Adoptive; Infiltration; Localization; Lymph Nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred C57BL; Oncology; Receptors, Chemokine; Skin Neoplasms - pathology; Solid tumors; Stroma; Tumors; Tumor homing; Solid tumors; Cancer immunotherapy; Adoptive T cell therapy; Chemokine receptors
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-023-03472-w

Localization is a crucial prerequisite for immune cell function and solid tumors evade immune control by modulating immune cell infiltration into the tumor stroma. Immunosuppressive cells like regulatory T cells are attracted, while cytotoxic CD8 + T cells are excluded. Engineering CD8 + T cells with chemokine receptors is a potent strategy to turn this mechanism of directed immune cell recruitment against the tumor. Here, we utilized fluorescent tagging to track the migratory behavior of tumor-specific T cells engineered with a library of all murine chemokine receptors in vivo. We then asked whether chemokine receptor-mediated redirection of antigen-specific T cells into tumors or tumor-draining lymph nodes showed superior anti-tumoral activity. We found that both targeting approaches showed higher therapeutic efficacy than control T cells. However, multiple receptors conveying the same homing pattern did not augment infiltration. Instead, in the MC38 colon carcinoma model, anti-tumoral efficacy as well as lymph node vs. tumor-homing patterns were mostly driven by CCR4 and CCR6, respectively. Overall, our data, based on fluorescent receptor tagging, identify the tumor-draining lymph node and the tumor itself as viable targets for chemokine receptor-mediated enhancement of adoptive T cell therapy.