Circulating tumor cells shielded with extracellular vesicle-derived CD45 evade T cell attack to enable metastasis.

Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45+ CTCs) that resisted T cell attack. A higher percentage of CD45+ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45+ tumor cells orchestrated an immunosuppressive milieu and CD45+ CTCs exhibited remarkably stronger metastatic potential than CD45- CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block "eat-me" signal.

Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on "eat-me" signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the "eat-me" signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3ß phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and "eat-me" signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1/PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer.

Introduction: Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed. Methods: This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated. Results: Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P<0.01; PFS: 2.00 vs 5.00 months, P<0.001, respectively). The HPD prediction nomogram included APTT (P<0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then, patients were divided into two groups by the "HPD score" calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%). Conclusions: The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.

M2-like macrophage-derived exosomes facilitate metastasis in non-small-cell lung cancer by delivering integrin αVß3.

Metastasis is the most prevalent cause of cancer deaths, and immunological components of the tumor microenvironment, especially tumor-associated macrophages (TAMs), play a vital role in cancer metastasis. However, the underlying mechanisms of TAMs on non-small-cell lung cancer (NSCLC) metastasis remain largely unexplored. Herein, we demonstrated that M2-like TAMs facilitate the migration and invasion of cancer cells in vitro and in vivo through intercellular delivery of M2-like macrophage-derived exosomes (M2-exos). Importantly, we found that M2-exos had considerably higher levels of integrin (ITG) αV and ß3. The impact of M2-like macrophage-mediated invasion and migration of NSCLC cells was clearly decreased when ITG αVß3 was blocked. Mechanistically, exosomal ITG αVß3 produced from M2-like macrophages successfully triggered the focal adhesion kinase signaling pathway in recipient cells, boosting the migratory and invasive abilities of NSCLC cells. Clinically, we found that metastatic NSCLC patients had greater ITG αV and ß3 expression, which was associated with a worse prognosis. This study reveals a novel mechanism by which M2-exos significantly increased NSCLC cell migration and invasion by delivering integrin αVß3. Exosomal ITG αVß3 can be used as a potential prognostic marker, and blocking ITG αVß3 could be a viable treatment option for preventing tumor metastasis.

KRAS mutation: from undruggable to druggable in cancer.

Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.

[Study on mRNA expression of the human novel gene NM23-H1B in ovarian tumor].

OBJECTIVE: To study the expression of the human novel gene NM23-H1B in ovarian cancer. METHODS: Forty-eight samples from patients with ovarian tumor at different clinical stages and 8 from normal ovaries were examined for NM23-H1B mRNA expression by using RT-PCR, northern blot and in situ hybridization. RESULTS: All samples expressed NM23-H1B mRNA through RT-PCR, while the level of expression in ovarian tumor was higher than that of normal ovary. The level of expression in early stage (stage I and II) cancer was higher than in advanced (stage III and IV) cancer. The results of northern blot showed that NM23-H1B was over expressed in ovarian cancer while low expressed in normal ovary or low malignant potential (LMP) ovarian cancer. In early stage carcinoma, the expression level was related with the differentiation of tumor cell. Well-differentiated cancer expressed NM23-H1B mRNA at comparatively higher level. The result of in situ hybridization showed that positive expression rate of NM23-H1B mRNA in ovarian cancer (100%, 40/40) was significantly higher than that in normal ovary (0/8) or LMP ovarian cancer (2/8). CONCLUSION: The novel gene NM23-H1B is related to ovarian cancer.