CD8+T cell exhaustion is a state of T cell dysfunction during chronic infection and tumor progression. Exhausted CD8+T cells are characterized by low effector function, high expression of inhibitory receptors, unique metabolic patterns, and altered transcriptional profiles. Recently, advances in understanding and interfering with the regulatory mechanisms associated with T cell exhaustion in tumor immunotherapy have brought greater attention to the field. Therefore, we emphasize the typical features and related mechanisms of CD8+T cell exhaustion and particularly the potential for its reversal, which has clinical implications for immunotherapy.
Lymphocyte-specific protein tyrosine kinase (LCK) is common in a variety of hematologic malignancies but comparatively less common in solid tumors. This study aimed to explore the potential diagnostic and prognostic value of LCK across tumors through integrative and comprehensive pan-cancer analysis, as well as experimental validation. Multiple databases were used to explore the expression, alteration, prognostic value, association with immune infiltration, and potential functional pathways of LCK in pan-cancers. The results were further validated by western blotting and qPCR of patient samples as well as tumor cell lines. High LCK expression typically represents a better prognosis. Notably, drug sensitivity prediction of LCK identified P-529 as a candidate for drug development. Gene Annotations (GO) and KEGG analyses showed significant enrichment of PD-L1 and the T-cell receptor pathway. The results from patient samples and tumor cell lines confirmed these conclusions in LIHC. In conclusion, LCK is differentially expressed in multiple tumors and normal tissues. Further analysis highlighted its association with prognostic implications, pan-cancer genetic alterations, and immune signatures. Our data provide evidence for a diagnostic marker of LCK and the possible use of LCK as a target for the treatment of tumors.
SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) functions as either a tumor promoter or tumor suppressor in several tumors. However, the detailed effect of SMURF2 on non-small cell lung cancer has not been fully understood. In this study, SMURF2 expression and its diagnostic value were analyzed. Co-Immunoprecipitation (Co-IP), proximity ligation assay (PLA), chromatin immunoprecipitation (ChIP) and nude mice tumor-bearing model were applied to further clarify the role of SMURF2 in lung cancer. SMURF2 expression was reduced in the tumor tissues of patients with NSCLC and high SMURF2 expression was significantly correlated with favorable outcomes. Furthermore, the overexpression of SMURF2 significantly inhibited lung cancer cell progression. Mechanistically, SMURF2 interacted with inhibitor of DNA binding 2 (ID2), subsequently promoting the poly-ubiquitination and degradation of ID2 through the ubiquitin-proteasome pathway. Downregulated ID2 in lung cells dissociates endogenous transcription factor E2A, a positive regulator of the cyclin-dependent kinase inhibitor p21, and finally induces G1/S arrest in lung cancer cells. This study revealed that the manipulation of ID2 via SMURF2 may control tumor progression and contribute to the development of novel targeted antitumor drugs.
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