LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures

Abstract

Despite the success of immunotherapy using checkpoint blockade, many patients with solid tumors remain refractory to these treatments. In human cancer, the experimental options to investigate the specific effects of antibodies blocking inhibitory receptors are limited and it is still unclear which cell types are involved. We addressed the question whether the direct interaction between T cells and tumor cells can be enforced through blocking a set of inhibitory receptors including PD-1, TIM-3, BTLA and LAG-3, blocked either individually or in dual combinations with the anti-PD-1 antibody, and to determine the condition that induces maximal T cell function preventing tumor cell proliferation. Using short-term Melan-A-specific or autologous re-stimulations, checkpoint blockade did not consistently increase cytokine production by tumor-derived expanded T cells. We next set up a 5-day co-culture assay with autologous melanoma cell lines and expanded tumor infiltrating T cells, originating from tumor specimens obtained from 6 different patients. Amongst all combos tested, we observed that blockade of LAG-3 alone, and more strongly when combined with PD-1 blockade, enforced T cell responses and tumor cell growth control. The combination of anti-LAG-3 plus anti-PD-1 acted through CD8 T cells and led to increased IFNγ production and cytotoxic capacity. Our results show that LAG-3 and PD-1 are regulating the direct interaction between tumor cells and autologous T cells, suggesting that therapy effects may be promoted by enhanced access of the corresponding blocking reagents to the tumor microenvironment. ARTICLE HISTORY

A combination of PD‑1/PD‑L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review)

“…Administration of PD-1 inhibitors only results in drug resistance promoting tumor progression. Co-administration with Tim-3 inhibitor restores anti-tumor effect and increases survival time (69,70). These findings imply that Tim-3 inhibitor may increase IFN-γ levels and increase T cell proliferation (13).…”

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

“…Patients with a response to combination therapy show an increase, relative to the level before the therapy, in the percentage of memory T cytotoxic lymphocytes with an EOMES+ (eomesodermin), CD69+, CD45RO+ phenotype. In addition, low expression of other negative immune checkpoints, most notably TIGIT and lymphocyte-activation gene 3 (LAG3), is observed on lymphocytes in patients responding to such treatment [ 38 , 39 , 40 , 41 ]. This phenomenon is not observed in patients responding to nivolumab monotherapy.…”

“…Patients receiving anti-PD-1 antibodies have increased expression of genes determining the cytolytic activity of lymphocytes (genes for granzymes A/B, KLRF1, FCRL3) [ 37 , 38 , 39 , 40 ]. In turn, increased expression of genes related to the capability of T lymphocytes of proliferation and production of specific cytokines (genes for Ki-67 and ICOS) is detected in patients receiving ipilimumab [ 38 , 39 , 40 , 41 ].…”

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia

“…LAG-3 signaling impairs T cell proliferation, cytokine production and cytolytic function while its expression on Tregs may promote immunosuppression [ 23 , 24 , 25 , 26 , 27 , 28 ]. Despite the functional consequence of LAG-3 blockade has extensively been studied in T cells, it has poorly been explored in NK cell function, although LAG-3 blockade failed to increase NK cell-mediated cytotoxicity in previous studies [ 29 , 30 , 31 ].…”