Gut-Associated Metabolites (GAMs) revitalize dysfunctional CD8⁺ T lymphocytes in Osteosarcoma

Authors

SAPRA, L., Bhardwaj, A., Paladhi, A., Farhat, A., Kaur, T., Kaur, S. P., Saini, C., Kumar, V. S., Khan, S. A., Srivastava, R. K.

Abstract

Osteosarcoma (OS) is one of the top ranking and deadliest primary malignant bone tumor of youngsters and adolescents. OS has poor prognostic features due to its immunosuppressive cold tumor microenvironment obstructing the anti-tumor effector functions of immune cells (including cytotoxic CD8 T lymphocytes). Recent developments have focused on the role of Gut Microbiota in modulating effector immune responses in various cancers. However the immunomodulatory role of gut microbiota and its derived gut-associated metabolites (GAMs) in OS still remains unclear. Here we report that peripheral CD8 T lymphocytes in osteosarcoma patients are less frequent in circulation hypo-producers of effector cytokines (IFNg and TNFa) and have compromised metabolic fitness. We characterized and investigated the effect of a panel of microbiota-derived GAMs on CD8 T lymphocytes confirming their immunomodulatory role with respect to CD8 T lymphocytes activation cellular metabolism and effector functions. Indole 3 lactic acid (ILA product of tryptophan metabolism) was observed to be the strongest immunostimulant among all the GAMs studied. ILA enhanced the anti-tumor effector functions of CD8 T lymphocytes through increased glucose uptake a higher mitochondrial bio-mass and increased production of IFNg and TNFa. Moreover ILA primed cytotoxic T lymphocytes exhibited considerably higher cytotoxicity and increased apoptosis of osteosarcoma cells (U2OS). Altogether our data demonstrates that ILA acts as a microbial derived immune modulator to metabolically reprogram and restore dysfunctional CD8 T lymphocytes against osteosarcoma. This study for the first time demonstrates the therapeutic potential of exploiting the nexus between Gut Immune Bone Tumor ternary as a safe and cost effective combinatorial immunotherapy against osteosarcoma.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

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