Together with signal 1 (Ag/MHC), signals 2 of co-stimulation (CD28) or counter-stimulation by CTLA-4 and PD-1 control the activation of specific effector Tc clones and their memory, or regulate anergy/abortion induction to prevent autoimmunity. Chronic Ag/MHC and low CD28 signals reduce the clonal diversity and memory. Further, they create TEX PD-1+Tim-3+ cells whose clonal expansion is a biomarker of cancer resistance serving as a prognostic marker. A portion of patients with metastatic cancer is cured with CTLA-4 mab, another develops autoimmunity reactions and a third suffers acquired resistance. Acquired resistance is aaributed to the PD-1/PD-L1 contra-stimulatory axis which is induced by IFN secreted during TEM responses against the tumor. PD-1 expression in TILs is proposed as a biomarker for dysfunctional TILs which are unable to fight cancer and resistant to aPD-1 therapy. However, PD-1 is expressed en TCM cells and is dispensable to create TEX cells as they can express an array of alternative contra-stimulatory checkpoint receptors (CpRs, such as Tim-3 or LAG-3). Together, it prompted us to investigate the role of Tim-3 in the generation of TEX and the acquired resistance to aPD-1 therapy, as well as the potential value of Tim-3 as a biomarker able to predict prognosis and immunotherapy responsiveness.

Las señales 1 (Ag/MHC) y 2 de co-estimulación CD28 o de contra-estimulación por CTLA-4 y PD-1 controlan la activación de clones Tc efectores específicos y su memoria, o anergia/aborto que evite autoinmunidad. Señales crónicas Ag/MHC altas y CD28 bajas abaten la diversidad y memoria y crean TEX PD-1+Tim-3+ cuya expansión clonal es un biomarcador de cáncer resistente a terapia empleado por su valor pronóstico. Una porción de pacientes con cáncer metastásico se cura con mab aCTLA-4, otra desarrolla autoinmunidad y una tercera sufre resistencia adquirida, atribuida al eje PD-1/PD-L1 inducido por IFN secretado por TEM durante su respuesta contra el tumor. Sin embargo, PD-1 se expresa en células TCM y es prescindible para crear TEX, ya que su desarrollo puede ser dirigido por Rs Contra-Estimuladores alternativos de otros puntos de control (CpRs, como Tim-3 o LAG-3). Por ello, investigamos el papel de Tim-3 en la génesis de TEX y en la adquisición de resistencia al tratamiento aPD-1, así como el hipotético valor de Tim-3 como biomarcador capaz de predecir el pronóstico y la respuesta eficiente a la inmunoterapia.

Grado en Medicina

48 p.