Activation of STING by the novel liposomal TLC388 enhances the therapeutic response to anti-PD-1 antibodies in combination with radiotherapy

Abstract

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.

Colorectal cancer-specific IFNβ delivery overcomes dysfunctional dsRNA-mediated type I interferon signaling to increase the abscopal effect of radiotherapy

“… 37 Pharmacological inhibitors of DNA damage response proteins, including ATR, ATM and PARP, 38 39 have been developed to enhance the therapeutic efficacy of RT. 18 However, increasing evidence indicates that the efficacy of RT largely relies on type I IFN-dependent innate and adaptive immunity. RT-induced dsDNA fragments are recognized by cGAS to trigger STING-mediated production of IFN-I and several proinflammatory cytokines for anticancer immunity.…”

“…This mixture was then used for specific cDNA amplification in a GeneAmp PCR system 2400 (Perkin Elmer, Waltham, Massachusetts, USA). 18 …”

“…This mixture was then used for specific cDNA amplification in a GeneAmp PCR system 2400 (Perkin Elmer, Waltham, Massachusetts, USA). 18 For mRNA quantification, real-time PCR was performed using a standard Rotor-Gene Q SYBR Green I Master protocol on a Rotor-Gene Q SYB system (Qiagen, QIAGEN Taiwan, Taipei, Taiwan). The 25 µL PCR included 2 µL cDNA, 12.5 µL 2×SyberGreen PCR Mix, 0.5 µL 10 µM forward primer, 0.5 L 10 µM reverse primer and 9.5 µL ddH 2 O.…”