Antitumor immunity in Ovarian and Colorectal cancer and adenosine-mediated T-cell suppression


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PhD thesis: a PhD thesis.
Antitumor immunity in Ovarian and Colorectal cancer and adenosine-mediated T-cell suppression
Coukos George
Harari Alexandre, Bobisse Sara, Vigano Selena
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Université de Lausanne, Faculté de biologie et médecine
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lmmunotherapy has transformed the cancer field. Aside from the overall improvement in survival, it has resulted in a more thorough understanding of the tumor microenvironment that extends beyond cancer cells.
Long-term remission has been one of immunotherapy's most notable achievements, promising a cure to around 20% of advanced melanoma patients treated with immune checkpoint inhibitors or adoptive T cell transfer (ACT) with tumor-infiltrating,lymphocytes (TILs); however, these successes have not been widely replicated in other solid tu mors.
This study focuses on two common tumor types for which immunotherapies have yet to provide a significant clinical benefit. Despite their association with T-cell infiltration and survival, ovarian (OvCa) and colon (CRC) adenocarcinomas are poorly immunogenic tumors. By studying TILs' phenotype and specificities, we investigated the potential ofT cell-based immunity in CRC and OvCa.
TILs were successfully expanded in vitro from most OvCa and CRC samples and neoantigen- (NeoAg) and tumor-specific T cells were identified consistently in TIL products. However, TIL product's tumor recognition was overall low. T-cell diversity loss and redistribution of T-cell clones during in vitro expansion, lead to a poor representation of tumor-reactive T celis in TIL products.
Interrogation of in situ clonally-expanded T-cell specificities revealed NeoAg- and tumor-reactive T celis undetected in in vitro-expanded TILs but their overall intratumoral frequency was low, and the vast majority ofT-cell specificities remained unknown.
TIL single-cell transcriptomic traits were studied in nine patients to better understand their diverse phenotypes and to identify key differences between tumor-reactive and bystander T cells, with the former displaying high expression of tissue-resident memory and exhaustion genes. These profiles led to the development of a tumor-reactive signature, which resulted in the successful and reliable identification of new tumor-reactive T cells and couId aid in the selection of relevant celis for therapy without the need for in vitro isolation and T-cell specificity testing.
T cells are critical players in anti-cancer immunity, but the powerful immunosuppressive pathways of the tumor microenvironment limit their effectiveness. Adenosine is an immunosuppressive metabolite that accumulates in the tumor microenvironment and promotes immune evasion.
We investigated the relative sensitivity of T-cell subsets to adenosine and found that its immunosuppressivè effects on human CD8 T cells mainly affect central memory CD8 T cells, most likely due to increased expression of the adenosine receptor (A2AR). A2AR activation increased protein kinase A impairing the mammalian target of rapamycin complex 1 pathway and leading to a reduction in T cell activity and metabolic fitness.
The current study reveals many of TIL-current ACT's challenges and contributes toits improvement by providing a clearer picture of the transcriptomic characteristics of tumor-reactive T celis. This detailed analysis will help identify relevant cells for T cell-based immunotherapies. Furthermore, our findings on adenosine-mediated immunosuppression suggest that this pathway can be targeted alongside T cell-based therapies to improve cancer immunotherapy.
Create date
19/09/2023 11:18
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20/09/2023 5:55
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