Unraveling a hidden player in lymphovascular invasion in bladder cancer.

Tumor invasion into the lymphatic vasculature represents a critical step during malignant progression of epithelial cancers. In this issue of Cancer Cell, Zheng et al. unravel how cancer-associated fibroblasts interact with lymphatic endothelial cells and the extracellular matrix to promote lymphatic tumor invasion and suggest that these processes could be treatment targets.

Oncologic outcomes after Total Mesometrial Resection (TMMR) or treatment according to current international guidelines in FIGO (2009) stages IB1-IIB cervical cancer: an observational cohort study.

Background: According to international guidelines, standard treatment (ST) with curative intent in cervical cancer (CC) comprises radical hysterectomy and pelvic lymphadenectomy in early stages (International Federation of Gynecology and Obstetrics (FIGO) 2009 IB1, IIA1), adjuvant chemoradiation is recommended based on risk factors upon final pathology. Definitive chemoradiation is recommended in locally advanced stages (FIGO 2009 IB2, IIA2, IIB). Total mesometrial resection (TMMR) with therapeutic lymph node dissection (tLND) without adjuvant radiation has emerged as a promising treatment. Here we compare oncologic outcome by TMMR + tLND or ST. Methods: In this observational cohort study, women treated according to international guidelines were identified in the population-based registries from Sweden and women treated with TMMR were identified in the Leipzig Mesometrial Resection (MMR) Study Database (DRKS 0001517) 2011-2020. Relevant clinical and tumour related variables were extracted. Recurrence-free survival (RFS) and overall survival (OS) by ST or TMMR was analysed with log-rank test, cumulative incidence function and proportional hazard regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for relevant confounders. Findings: Between 2011 and 2020, 1007 women were included in the final analysis. 733 women were treated according to ST and 274 with TMMR. RFS at five years was 77.9% (95% CI 74.3-81.1) and 82.6% (95% CI 77.2-86.9) for the ST and TMMR cohorts respectively (p = 0.053). In early-stage CC, RFS was higher after TMMR as compared to ST, 91.2% vs 81.8% (p = 0.002). In the adjusted analysis, TMMR was associated with a lower hazard of recurrence (HR 0.39; 95% CI 0.22-0.69) and death (HR 0.42; 95% CI 0.21-0.86) compared to ST. The absolute difference in risk of recurrence at 5 years was 9.4% (95% CI 3.2-15.7) in favor of TMMR. In locally advanced CC, no significant differences in RFS or OS was observed. Interpretation: Compared to ST, TMMR without radiation therapy was associated with superior oncologic outcomes in women with early-stage cervical cancer whereas no difference was observed in locally advanced disease. Our findings together with previous evidence suggest that TMMR may be considered the primary option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment. Funding: This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden).

Different contractility modes control cell escape from multicellular spheroids and tumor explants.

Cells can adapt their active contractile properties to switch between dynamical migratory states and static homeostasis. Collective tissue surface tension, generated among others by the cortical contractility of single cells, can keep cell clusters compact, while a more bipolar, anisotropic contractility is predominantly used by mesenchymal cells to pull themselves into the extracellular matrix (ECM). Here, we investigate how these two contractility modes relate to cancer cell escape into the ECM. We compare multicellular spheroids from a panel of breast cancer cell lines with primary tumor explants from breast and cervical cancer patients by measuring matrix contraction and cellular spreading into ECM mimicking collagen matrices. Our results in spheroids suggest that tumor aggressiveness is associated with elevated contractile traction and reduced active tissue surface tension, allowing cancer cell escape. We show that it is not a binary switch but rather the interplay between these two contractility modes that is essential during this process. We provide further evidence in patient-derived tumor explants that these two contractility modes impact cancer cells' ability to leave cell clusters within a primary tumor. Our results indicate that cellular contractility is an essential factor during the formation of metastases and thus may be suitable as a prognostic criterion for the assessment of tumor aggressiveness.

A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity.

Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.

TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.

A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies. SIGNIFICANCE: STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.