Interference with pathways activated by topoisomerase inhibition alters the surface expression of PD‑L1 and MHC I in colon cancer cells

Hassan, Mohamed; Trung, Vu; Bedi, Deepa; Shaddox, Sage; Gunturu, Dilip Reddy; Yates, Clayton; Datta, Pran K.; Samuel, Temesgen

doi:10.3892/ol.2022.13628

Cited by 6 publications

(8 citation statements)

References 37 publications

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“…Genotoxic chemotherapies, including TOP1 inhibitors, have been shown to upregulate tumor PD-L1 expression and confer clinical benefits when combined with ICIs [ 41 , 42 ]. Therefore, we investigated whether TLC388 can directly increase tumor PD-L1 expression.…”

Section: Resultsmentioning

confidence: 99%

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

Chen,

Lin,

Hong

et al. 2024

Cancer Immunol Immunother

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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.

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Section: Resultsmentioning

confidence: 99%

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

Chen,

Lin,

Hong

et al. 2024

Cancer Immunol Immunother

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“…The antibody-drug conjugates are explored as drug payloads against TOPI and target selective tumor antigens, predominantly TROP-2. Emerging evidence supports the link between chemotherapeutic drugs, as topo-acting drugs such as MTX may upregulate major histocompatibility class I (MHC-I) antigen processing and presentation [209,210]. In turn, propositions of the combinatorial approaches that can combine topo-acting drugs and immune checkpoint inhibitor therapies (ICIT) such as the PD-1/PD-L1 [PD-(L)1] blockade are warranted [209][210][211][212].…”

Section: Immune Checkpoint Inhibitors and Topo-active Drugsmentioning

confidence: 99%

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Sharma,

Bahot,

Sekar

et al. 2024

Cancers

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In recent years, the emergence of cancer drug resistance has been one of the crucial tumor hallmarks that are supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters, and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often result in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores the use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

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“…Genotoxic chemotherapies, including topoisomerase I inhibitors, have been shown to upregulate tumor PD-L1 expression and confer clinical bene ts when combined with ICIs (32,33). Therefore, we investigated whether TLC388 cells can directly increase tumor PD-L1 mRNA expression.…”

Section: Low-dose Lc388 Upregulated Cancer-intrinsic Pd-l1 Expression...mentioning

confidence: 99%

Activation of STING by the Novel Liposomal TLC388 Enhances the Therapeutic Response to Anti-PD-1 Antibodies in Combination with Radiotherapy

Chen,

Lin,

Hong

et al. 2024

Preprint

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Rectal cancer constitutes 30–40% of colorectal cancer (CRC) cases and is a major global cause of cancer-related mortality. The main therapeutic approach for locally advanced rectal cancer patients is chemoradiotherapy (CRT), which controls tumor growth and diminishes distant metastasis. Nevertheless, 30–40% of patients exhibit a partial response to CRT because of the detrimental effects of drug toxicity and because of the potential risk of delaying surgery. In our study, we discovered that the novel topoisomerase I inhibitor lipotecan (TLC388) can induce immunogenic cell death (ICD), leading to the release of damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT. Lipotecan enhances cancer immunogenicity, stimulating the antitumor immune response that promotes the infiltration of immune cells within the tumor microenvironment (TME), both in vitro and in vivo. Collectively, these findings highlight the capacity of lipotecan to reshape the tumor microenvironment, thereby stimulating anticancer immune responses, as well as holding promise for enhancing the therapeutic efficacy of neoadjuvant CRT in patients with local advanced rectal cancer.

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Interference with pathways activated by topoisomerase inhibition alters the surface expression of PD‑L1 and MHC I in colon cancer cells

Cited by 6 publications

References 37 publications

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

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

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Activation of STING by the Novel Liposomal TLC388 Enhances the Therapeutic Response to Anti-PD-1 Antibodies in Combination with Radiotherapy

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