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Supplementary Data from Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.

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Checkpoint molecules like CTLA-4 are important regulators of tumor-specific tolerance, and monoclonal antibodies that block this class of molecules have emerged as important therapeutic modalities in multiple cancer types. Recent data suggest that tumor infiltrating, non-functional ("exhausted") CD8 cells may express more than one checkpoint molecule, implying a more subtle control system for modulating CD8 T cell function in vivo. Based on their frequent co-expression on tumor-infiltrating lymphocytes, we investigated the relative roles of PD-1 (programmed death - 1) and LAG-3 (lymphocyte activation gene -3) in tumor tolerance. Single knockout (KO) mice lacking either of these genes were relatively unaffected, with PD-1 KO mice developing a late-onset strain-specific myocarditis. However, double knockout mice (DKO) lacking both PD-1 and LAG-3 developed early autoimmune pathology, with infiltrating lymphocytes present in multiple organs, and eventual lethality. More significantly, DKO mice spontaneously rejected the poorly immunogenic B16 melanoma, while rejection was not observed when either PD-1 or LAG-3 was knocked out individually. Moreover, established tumors in wild-type mice could be cured by combined treatment anti-PD-1 and anti-LAG-3 antibodies, while single antibody treatment was sufficient only to delay tumor outgrowth. Taken together, these data demonstrate a previously unappreciated synergy between these two checkpoint molecules in tumor-specific tolerance, and suggest a novel combinatorial strategy for cancer immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-251. doi:10.1158/1538-7445.AM2011-LB-251