LIM and SH3 protein 1 deficiency confers resistance to cytotoxic lymphocyte-mediated lysis and immunotherapy in gastric cancer by disrupting cytoskeleton dynamics

Vollständiger Abstract

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Background A substantial amount of research has been dedicated to the mechanisms by which tumor cells evade immune system recognition and manipulate the immune microenvironment to facilitate immune escape. Recent studies have shown that viruses and tumors can protect themselves from immune cytotoxicity by remodeling the actin cytoskeleton. However, cytoskeleton-mediated immune resistance and the specific cytoskeleton-related proteins involved require further research. Methods Single-cell RNA sequencing was used to identify cytoskeleton-related genes associated with the response to anti-programmed cell death protein 1 (PD-1) therapy across four digestive tumors. Immunohistochemistry was used to detect LASP1 expression in gastric cancer and analyze its prognostic value for survival and anti-PD-1 response. The impact of LASP1 deficiency on tumor response to anti-PD-1 treatment and cytotoxic lymphocyte-mediated lysis was determined in vivo and in vitro. Live-cell imaging was used to compare actin cytoskeletal dynamics at the immunological synapse between LASP1-deficient and mock tumor cells. Molecular mechanisms underlying LASP1-mediated immune-resistance were dissected using co-immunoprecipitation, immunofluorescence, domain deletion complementation, and Laurdan staining. Results The deficiency of LASP1 in gastric cancer affected the sensitivity of tumor cells to immunotherapy and induced cytotoxic lymphocytes exhaustion. LASP1 may act as a scaffold protein to regulate the Arp2/3 complex and remodel the cytoskeleton at the immunological synapses. LASP1 deficiency in tumor cells impairs lytic immunological synapse function by disrupting cytoskeletal dynamics-mediated cell membrane lipid organization at the immunological synapse. Finally, simvastatin combined with anti-PD-1 therapy reversed immunotherapy resistance in LASP1-deficient tumors. Conclusions The deficiency of LASP1 in tumors mediates immunological synapse dysfunction by affecting cytoskeletal dynamics-mediated cell membrane lipid organization, thus enabling tumors to protect themselves from immune cytotoxicity and immunotherapy.