Nilotinib boosts the efficacy of anti-PDL1 therapy in colorectal cancer by restoring the expression of MHC-I.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. METHODS: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. RESULTS: Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. CONCLUSION: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.

Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.

Immune checkpoint blockade therapy has demonstrated significant therapeutic effects in certain types of cancers. However, there is limited reporting on the influence of physical activity on its efficacy. This study aimed to investigate the impact of physical activity on anti-PDL-1-mediated immune checkpoint therapy and the interplay of immune cells therein. HePa1-6 tumor-bearing mice were treated with anti-PDL-1 in conjunction with physical activity to assess tumor progression. Flow cytometry was utilized to analyze immune cell infiltration and differentiation levels within the tumor. The expression of HIF-a/CEACAM1 within the tumor due to physical activity was evaluated. HePa1-6 cells with high CEACAM1 expression were validated in mice to determine their inhibitory effects on immune cell proliferation and differentiation. A CD3/CEACAM1 chimeric antibody was developed for treating CEACAM1-overexpressing tumors, and flow cytometry was employed to assess T-cell response. Physical activity enhanced the efficacy of anti-PDL1 by suppressing the HIF-a/CEACAM1 axis within the tumor. In vivo experiments revealed that tumors with high CEACAM1 expression decreased infiltration and activation of CD8 + T cells within the tumor, suppressing T cell cytotoxicity without affecting Treg infiltration. In vitro, high CEACAM1 expression impacted the proliferation and activation of CD8 + T cells in a co-culture system. The constructed CD3/CEACAM1 chimeric antibody significantly activated the TCR within CEACAM1-overexpressing tumors and inhibited tumor progression. The findings suggest that physical activity augments the effectiveness of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.