Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer

Neoplasias genitales; Inmunoterapia; Linfocitos TNeoplàsies genitals; Immunoteràpia; Limfòcits TGenital neoplasms; Immunotherapy; T-LymphocytesBackground Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. Methods To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. Results We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1− and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1− or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. Conclusions Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity.AG was funded by the Comprehensive Program of Cancer Immunotherapy and Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021), the La Fundació La Marató de TV3 (201919-30; identification number 488/C/2019), the Spanish Ministry of Science and Innovation (PID2020-118529RB-100) and Instituto de Salud Carlos III (CP15/00058). We thank the CERCA Programme/Generalitat de Catalunya for institutional support. JP was supported by the Beatriu de Pinós programme (BP 2018), cofounded by the Agency for Management of University and Research Grants (AGAUR) and European Union's Horizon 2020. HUB-ICO-IDIBELL Biobank received support from Instituto de Salud Carlos III (PT20/00171) and by Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncologia de Catalunya (XBTC)

Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer

Background: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. Methods: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. Results: We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1- and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1- or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. Conclusions: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity

Poesía femenina hispanoamericana : (nómina incompleta)

Apparebit repentina dies ; Lluvia sobre las lomas / Alfonsa de la Torre - Alabanza de María en su embarazo / Pilar Paz Pasamar - Pájaro de tristeza ; ¿Así la muerte? / Concha Zardoya - Poema de mi sombra ; Gran ciudad / Pura Vázquez - Yo ; ¿Qué será la muerte? / Susana March - Anulación ; Vencida por el ángel / Ángela Figuera Aymerich - No es más que una pared ; He pisado la hierba / Ester de Andreis - La tormenta ; La fiera / Juana García Noreña - Angustia / Mercedes Chamorro - La posesión ; Cántico de María Sola / Josefina Romo Arregui - Trino, Ofrecimiento / Clemencia Laborda - Hombres descalzos ; ¿Acaso duerme el ángel? / Ana Inés Bonnin - Madre ; Meditando la mujer ahora / Carmen Conde - Oración de Mujer / Eugenia Serrano - ¡Ay como temo!, Caminaba yo ; No creo en tí ; Dios / Guadalupe Amor - Vida-garfio ; La hora / Juana de Ibarbourou - Hombre ; El viento de la angustia / Clara Silva - Ahora tengo la vida / Josefina de Cepeda - Tierra morena / María Elvira Piwonka - Agua escondida ; Todavía ; Abrazo / Dulce María Loynaz - Fin /Alicia Eguren - Alfonsina en el mar / María Dhialma Tiberti - El poeta va solo / Margarita Michelena -Tú bien lo sabes / Marta Sánchez Fuentes - Volverlo a ver ; Ausencia / Gabriel Mistral - Lívido arcángel / Sara de Ibáñez - Inquietud ; Nadie / Helena Muñoz - La demente en la puerta de la iglesa / Fina García Marru