Immunotherapeutic strategies with meta tyrosine and inhibitors of p38 pathway in local recurrences and metastatic murine tumor models

CHIARELLA, PAULA; RUGGIERO, RAÚL A.; DUARTE, ALEJANDRA; VERMEULEN, MÓNICA; MONTAGNA, DANIELA R.; REARTE, BÁRBARA

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2020

SAIC- SAI

Immune-checkpoints inhibitors (ICI) have been considered the most promising anti-tumor immunotherapy in the last years. However, ICI were effective to restrain only incipient experimental tumors. Failures of immunotherapy may be associated with the fact it would produce weak immune responses that would promote rather than inhibit tumor growth upon activation of TLR4 and p38 signaling pathways. Herein, we compare the effect of ICI on the growth of both incipient and residual tumors. Then, we have combined ICI with meta-tyrosine (m-tyr) - which, according to previous results, might restrain immune checkpoints not counteracted by classical ICI - and SB 202190, a selective inhibitor of p38, to counteract the tumor-immune-stimulation. We have used two murine tumor models: a local recurrence after subcutaneous (s.c.) MC-C fibrosarcoma (about 800 mm3) was surgically excised leaving intact the underlying skin; and a metastatic model after s.c. LMM3 mammary carcinoma (LMM3) was radically removed when spontaneous lung metastases were already established. One day after surgery, mice were treated with ICI (anti-CTLA-4 for MC-C, or anti-PD-L1 for LMM3) or a combination of ICI with m-tyr and SB 202190. Local recurrences and metastases were not inhibited by the very same treatments that strongly inhibited incipient tumors (p < 0.001). In fact, growth of local recurrences upon treatment with ICI was enhanced similarly that mid-sized tumors from which residual tumors derived (p