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Lack of effector cell function and altered tetramer binding of tumor-infiltrating lymphocytes
Ulrike Blohm1, Evelyn Roth, Kathrin Brommer
1Institute of Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Hermann-Herdfer-Strasse 11, D-79104 Freiburg, Germany.
Abstract:
Tumor-specific CD8 T cell responses to MCA102 fibrosarcoma cells expressing the cytotoxic T cell epitope gp33 from lymphocytic choriomeningitis virus were studied. MCA102(gp33) tumors grew progressively in C57BL/6 mice, despite induction of peripheral gp33-tetramer(+) T cells that were capable of mediating antiviral protection, specific cell rejection, and concomitant tumor immunity. MCA102(gp33) tumors were infiltrated with a high number ( approximately 20%) of CD11b(+)CD11c(-) macrophage-phenotype cells that were able to cross-present the gp33 epitope to T cells. Tumor-infiltrating CD8 T cells exhibited a highly activated phenotype but lacked effector cell function. Strikingly, a significant portion of tumor-infiltrating lymphocytes expressed TCRs specific for gp33 but bound MHC tetramers only after cell purification and a 24-h resting period in vitro. The phenomenon of "tetramer-negative T cells" was not restricted to tumor-infiltrating lymphocytes from MCA102(gp33) tumors, but was also observed when Ag-specific T cells derived from an environment with high Ag load were analyzed ex vivo. Thus, using a novel tumor model, allowing us to trace tumor-specific T cells at the single cell level in vivo, we demonstrate that the tumor microenvironment is able to alter the functional activity of T cells infiltrating the tumor mass.
Insights
Tumor microenvironments can impair CD8 T cell function, even when T cells are specific for tumor antigens. This study reveals that tumor-infiltrating T cells may appear non-functional due to the tumor microenvironment, not a lack of specificity.
Area of Science:
- Immunology
- Cancer Biology
- T cell immunology
Background:
- Tumor-specific CD8 T cell responses are crucial for cancer immunity.
- However, the tumor microenvironment (TME) often suppresses anti-tumor immunity.
- The functional status of T cells within the TME requires further investigation.
Purpose of the Study:
- To investigate the functional state of tumor-specific CD8 T cells infiltrating a fibrosarcoma model.
- To explore the impact of the tumor microenvironment on T cell effector function.
- To characterize the phenomenon of 'tetramer-negative T cells' in the context of tumors.
Main Methods:
- Utilized a murine fibrosarcoma model (MCA102) engineered to express a viral epitope (gp33).
- Analyzed tumor-infiltrating lymphocytes (TILs) for phenotype, activation status, and effector function using flow cytometry and MHC tetramer staining.
- Investigated antigen presentation by tumor-infiltrating myeloid cells.
Main Results:
- MCA102(gp33) tumors grew progressively despite the presence of functional peripheral T cells.
- Tumors were infiltrated by activated CD8 T cells that paradoxically lacked effector function.
- A significant population of tumor-infiltrating lymphocytes exhibited T cell receptor (TCR) specificity but were initially 'tetramer-negative', requiring in vitro rest to bind tetramers.
- This 'tetramer-negative' state was also observed in T cells from other high antigen load environments.
Conclusions:
- The tumor microenvironment actively suppresses the function of tumor-specific CD8 T cells.
- The observed 'tetramer-negative' phenotype suggests a reversible functional impairment induced by the TME.
- This study highlights the critical role of the TME in dictating T cell efficacy in cancer immunology.