Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

Abstract

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here we reveal extensive co-expression of PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathological sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3−/−Pdcd1−/− mice demonstrated markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. Additionally, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…MC38 (kindly provided by Dr. Charles Drake) and luciferase-expressing GL261 (GL261-Luc, purchased from Caliper Life Sciences) cells are syngeneic murine-derived colon adenocarcinoma and glioma cell lines, respectively, that are sensitive to PD-1 blockade in vivo . 18–21 Both cell lines were grown in Dulbecco’s Modified Eagle Medium (DMEM, Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS, Gemini Bio-Products) and 1% penicillin-streptomycin (Quality Biological) at 37°C in a humidified incubator maintained at 5% CO 2 and 5% O 2 . Additionally, GL261-Luc cells were kept under selection conditions with culture media containing 100 ug/mL G418 sulfate antibiotic (Corning).…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…The strongest evidence that exhausted cells retain the ability to mount a potent effector response comes from the many studies in which strong anti-tumor or anti-viral immunity could be restored by blocking PD-1/PD-L1 interaction alone or in combination with targeting other receptors [46][47][48][49][50][51][52] . This approach of antibody-mediated "checkpoint blockade" is now increasingly used to treat patients with cancer and its impact on chronic infections in humans is being evaluated (Box 1).…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Besides, the function of tumor antigen-specific CD8 þ T cells was significantly augmented by dual blockade of LAG3 and PD-1, thus, possibly represented a highly promising immune-based strategy in cancer treatment. 38,39 There are multiple clinical trials trying to translate combination modality into clinical practice (Table 1).…”