Enriquecimiento de linfocitos t específico de tumor en base a la expresión de la proteína de muerte celular programada 1 (pd-1): Implicación en la terapia celular adoptiva del cáncer de ovario con linfocitos T infiltrantes de tumor
- Autores: Diego Salas Benito
- Directores de la Tesis: Sandra Hervás Stubbs (dir. tes.), Mariano Ponz-Sarvise (codir. tes.)
- Lectura: En la Universidad de Navarra ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Alena Gros Vidal (presid.), Miguel Fernández de Sanmamed Gutierrez (secret.), Araceli Beatriz Martín Antonio (voc.), Antonio González Martín (voc.), Andres Redondo Sánchez (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina Aplicada y Biomedicina por la Universidad de Navarra
- Materias:
- Texto completo no disponible (Saber más ...)
- Resumen
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1. TILs can be used in adoptive T-cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TILs in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TILs without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TILs before expansion, only T-cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TILs, specifically recognized tumor cells. The fold expansion of PD-1. CD8 TILs was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TILs. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Overall, our data provide a rationale for the use of PD-1-selected TILs in ACT.
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) has received increasing attention for the treatment of ovarian cancer (OC). The antitumor reactivity of the final TIL product determines the success of this therapy. The use of markers, such as PD-1, allows the identification of tumor-specific TILs in melanoma, but exploratory studies in OC do not seem to confirm these data. On the other hand, the finding of predictive biomarkers that help identifying those patients capable of rendering tumor-reactive TILs is also necessary to implement this therapy. To meet these gaps, PD-1- and PD-1+ CD8 TILs were isolated from 10 resected OC and, after expansion, TIL products were tested against autologous tumor cells. Tumor-reactive TILs were detected in 5/10 patients and they were exclusively present in cells derived from the PD-1+ fraction. Flow cytometry studies revealed that fresh tumors from patients rendering tumor-reactive TILs presented significantly higher frequency of CD137+ cells within the PD1+CD8+ subset. Multiplexed immunofluorescence supported this finding, being more notable in intraepithelial CD8 TILs. Fresh-tumor gene expression profile (GEP) showed that patients rendering tumor-reactive TILs exhibited significantly higher T-cell inflamed GEP. Despite no correlation between tumor mutational burden (TMB) and GEP, both parameters stratified patients. Interestingly, patients with high values of TMB and/or GEP rendered tumor-reactive TILs, whereas those with low TMB and GEP did not. Our results have important implications to generate final TIL products with higher predictable antitumor activity, as well as to identify OC patients eligible for TIL therapy.
