L-Selectin Enhanced T Cells Improve the Efficacy of Cancer Immunotherapy

Abstract

The homing molecule, L-selectin (CD62L), is commonly used as a T cell activation marker, since expression is downregulated following engagement of the T cell receptor. Studies in mice have shown that CD62L + central memory T cells are better at controlling tumor growth than CD62L − effector memory T cells, while L-selectin knockout T cells are poor at controlling tumor growth. Here, we test the hypothesis that T cells expressing genetically modified forms of L-selectin that are maintained following T cell activation (L-selectin enhanced T cells) are better at controlling tumor growth than wild type T cells. Using mouse models of adoptive cell therapy, we show that L-selectin enhancement improves the efficacy of CD8 + T cells in controlling solid and disseminated tumor growth. L-selectin knockout T cells had no effect. Checkpoint blockade inhibitors synergized with wild type and L-selectin enhanced T cells but had no effect in the absence of T cell transfers. Reduced tumor growth by L-selectin enhanced T cells correlated with increased frequency of CD8 + tumor infiltrating T cells 21 days after commencing therapy. Longitudinal tracking of Zirconium-89 ( 89 Zr) labeled T cells using PET-CT showed that transferred T cells localize to tumors within 1 h and accumulate over the following 7 days. L-selectin did not promote T cell homing to tumors within 18 h of transfer, however the early activation marker CD69 was upregulated on L-selectin positive but not L-selectin knockout T cells. L-selectin positive and L-selectin knockout T cells homed equally well to tumor-draining lymph nodes and spleens. CD69 expression was upregulated on both L-selectin positive and L-selectin knockout T cells but was significantly higher on L-selectin expressing T cells, particularly in the spleen. Clonal expansion of isolated L-selectin enhanced T cells was slower, and L-selectin was linked to expression of proliferation marker Ki67. Together these findings demonstrate that maintaining L-selectin expression on tumor-specific T cells offers an advantage in mouse models of cancer immunotherapy. The beneficial role of L-selectin is unrelated to its' well-known role in T cell homing and, instead, linked to activation of therapeutic T cells inside tumors. These findings suggest that L-selectin may benefit clinical applications in T cell selection for cancer therapy and for modifying CAR-T cells to broaden their clinical scope.

Identification of a tumor microenvironment-related gene signature to improve the prediction of cervical cancer prognosis

“…Vlad et al revealed that CD62L is downregulated in chronic lymphocytic leukemia and associated with disease progression [ 34 ]. Additionally, CD62L can enhance the efficacy of tumor immunotherapy for cancer treatment [ 35 ]. In bladder cancer, the serum level of SELL has been found to be useful as a tool for diagnostic staging and grading [ 36 ].…”

Altered Cell Adhesion and Glycosylation Promote Cancer Immune Suppression and Metastasis

“…Sustained L-selectin expression on NK cells was shown to control tumor progression (39). Recently, the role of L-selectin on T cells was investigated in a transgenic mouse model that expressed non-cleavable L-selectin (40). T cells with constitutive expression of L-selectin suppressed lung metastasis.…”

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

“…The existence of PD-1+ TIL cells may indicate potential sensitivity to ICI. Preclinical data suggest that the combination of ICI with TIL-ACT can synergistically increase T cell cytolytic ability, effector molecule synthesis, and tumor infiltration, leading to greater tumor control and improved survival [ 95 , 96 , 97 , 98 ]. In one case study, combinatory treatment of TIL and a PD-1 inhibitor led to complete regression of all six metastases in a patient with metastatic breast cancer [ 99 ].…”