| Colon cancer is the third most common cancer diagnosed in the world,and its incidence rate and mortality are increasing year by year.Immune checkpoint blockade(ICB)therapy has generated considerable success in microsatellite-instability(MSI)colon cancer,but has no effects on microsatellite-stable(MSS)colon cancer patients.According to the literature,one reason for these effects is that MSS colon cancers contain few mutations and have low immunogenicity.To improve the efficacy of immune checkpoint blocking therapy,researchers have tried to combine it with chemotherapy.Conventional chemotherapy doses are administered at maximumtolerated doses,which may lead to severe immunosuppression,however the efficacy of ICB therapy depends on the tumor infiltration of lymphocytes.This is a reason why chemotherapeutic drugs couldn’t synergize with ICB.However,several drugs such as oxaliplatin induce immunogenic tumor cell death,improve colon cancer immunogenicity and stimulate the acquired immune response and trigger the antitumor response.Therefore,these immunogenic chemotherapy drugs could improve ICB against tumors.T cell immune receptor with Ig and ITIM domains(TIGIT)is currently one of the most studied immune checkpoints.In our previous work,we found that CD8+T cells in colon cancer patients highly expressed TIGIT as did tumor-infiltrating natural killer(NK)cells.Anti-TIGIT mAb reversed CD8+T cells and NK cells exhaustion and suppressed tumor growth.We treated colon cancer cells with oxaliplatin combined with anti-TIGIT mAb to hope for better effects on MSS colon cancer growth inhibition.We generated the following results at combined treatment of oxaliplatin and anti-TIGIT mAb on CT26-bearing mice(MSS type colon cancer):We found that maximum tolerated dose OX reduced tumor growth but failed to synergize with anti-TIGIT therapy.After reducing the dosage and frequency of oxaliplatin,combination therapy with anti-TIGIT and OX suppressed tumor growth and significantly increased survival.The therapeutic effect was significantly better in the combination treatment group than in the TIGIT-blocking antibody treatment group.Further analysis of tumor-infiltrating lymphocytes revealed that the combination of low-dose oxaliplatin and anti-TIGIT antibody can increase the infiltration of CD45+cells and CD8+TILs into tumors.We depleted CD8+T cells in CT26-bearing mice and found that the deficiency of CD8+T cells significantly led to accelerated tumor growth.Additionally,TIGIT blockade combined with low-dose OX lost the inhibition of tumor growth in CD8+T deficient mice compared to that in untreated mice.These results indicate that Low-dose oxaliplatin combined with anti-TIGIT antibody can promote the efficacy of colon cancer and increase tumor infiltration of immune cells with synergistic efficacy depending on CD8+T cells.When the dose of oxaliplatin was increased from low dose to full dose,the synergism of the combination treatment wasn’t observed;which could not delay tumor growth or increase overall survival.Full-dose oxaliplatin induced severe immunosuppression.In the mice that received full-dose oxaliplatin treatment with t anti-TIGIT mAb,significant reductions in white blood cells(WBCs)and peripheral blood lymphocytes were observed.The absolute numbers of tumorinfiltrating lymphocytes(TILs)were also decreased significantly.Furthermore,cisplatin did not cause tumor cells to release death-associated damage-associated molecular patterns and did not lead to the immunogenic death of tumor cells.In vivo,we also found that the combination of cisplatin with the TIGIT-blocking antibody did not lead to a significant change in the tumor growth rate compared with the control group and there was no synergistic anti-tumor effect between the drugs.This result indicates that non-immunogenic platinum chemotherapy drug(cisplatin)combined with anti-TIGIT antibody has no synergistic anti-tumor effect.Our study shows that the dose and regimen of combination therapy should be optimized to alleviate the potential antagonistic effect of immunosuppressive chemotherapy during immunotherapy and that chemotherapeutic drugs should be rationally selected to enhance tumor immunogenicity and to sensitize tumors resistant to ICB blockade treatment.Our study provides a new approach for the clinical treatment of MSS tumors and has guiding significance. |
