Efecto del bloqueo del punto de control inmunológico CTLA-4 sobre el crecimiento de dos tumores murinos de distinta inmunogenicidad

STRAZZA, ARIEL R.; RUGGIERO, RAúL A.; MONTAGNA, DANIELA R.; DRAN, GRACIELA; CHIARELLA, PAULA

Buenos Aires

Jornada; XXXI Jornadas Multidisciplinarias de Oncología del Instituto Roffo; 2016

Instituto Angel Roffo

CTLA-4 is an immune checkpoint expressed in T reg and activated T cells that transmits inhibitory signals to T cells and down-regulates immune responses. On this basis, there is a growing interest in the possible therapeutic benefits of blocking CTLA-4 as a means of enhancing immune responses against cancer. In fact ipilimumab ? a monoclonal anti-CTLA-4 antibody ? was recently approved for the treatment of human advanced melanoma. However, despite these promissory expectations, most experimental studies in this topic were performed in mice bearing strongly immunogenic chemically-induced tumors that are not the best models for clinical cancer. Herein, we have studied the effect of an antibody against CTLA-4 on the growth of two murine tumors displaying widely different degrees of immunogenicity: the strongly immunogenic methylcholanthrene-induced MC-C fibrosarcoma and the spontaneous LMM3 carcinoma displaying undetectable immunogenicity. Tumor-bearing mice (n = 6 mice per group) received 3 doses of 100 ìg i.p. of anti-CTLA-4 antibody each 4 days starting at day 3, 10 or 17 after the s.c. inoculum with 5x105 MC-C or LMM3 tumor cells, that is when the tumor was incipient (I), medium (M) or large (L). Results were expressed as tumor volume (mm3) [media ± SE] at day 35 of tumor growth. MC-C: Control Group (without treatment): 2,027± 63; Treated Groups: I: 314 ± 74 (p < 0.001 vs. Control); M: 2,085 ± 273; G: 3119 ± 286 (p < 0.05). LMM3: Control Group: 2,142 ± 104; Treated Groups: I: 2797 ± 204 (p < 0.05); M: 1929 ± 129; G: 2071 ± 161. Our results revealed that CTLA-4 blocking was therapeutically efficient against small-sized strongly immunogenic tumors only. On large immunogenic and on small non-immunogenic tumors, a slight but significant tumor enhancement was observed. Presumably, the combination of CTLA-4 blocking with other approaches such as PDL-1 immune checkpoint blocking, could eventually expand the antitumor effects of these antitumor immunological strategies.