Cell Reports

Older age is a strong risk factor for several diseases, including cancer. In cancer, older age is also frequently associated with a more aggressive, treatment-refractory tumor phenotype. The etiology and biology of age-associated differences among cancers are poorly understood. To address this knowledge gap, we sought to delineate the differences in tumor molecular characteristics between younger and older patients across a variety of tumor types. We found that tumors in younger and older patien...

Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers, with some patients succumbing to the disease within weeks of diagnosis. Although a subset of patients with ATC with BRAFV600E mutation respond to the monomeric type I RAF inhibitor (RAFi) dabrafenib in combination with MEK inhibitor (MEKi) trametinib, most rapidly develop adaptive or acquired resistance. These patients, along with those who do not harbor the BRAFV600E alteration, have limited treatment options. To understan...

De novo protein design is becoming a powerful tool for diagnostic and therapeutic agent development. However, direct evidence remains lacking for dynamic binding of de novo designed binders both in vivo and clinical settings. PD-L1, quantified via immunohistochemistry, represents the most widely validated, utilized, and accepted biomarker for PD-1/PD-L1 therapy. Due to the spatial heterogeneity and temporal dynamics of PD-L1 expression, this molecule represents an ideal target for exploring the ...

Identifying conserved, immunogenic proteins that confer protection against Streptococcus pneumoniae colonisation could enable development of serotype-independent vaccines. We analysed baseline samples from 86 healthy adults experimentally challenged with pneumococcal serotypes 6B or 15B to investigate whether immune responses to 75 universally expressed pneumococcal proteins associated with protection against colonisation. We measured serum IgG using a novel Luminex assay and cytokine responses...

In syngeneic murine breast cancer models, poly(ADP-ribose) polymerase inhibitor (PARPi) and anti-PD-L1 combinations induce deep, sustained responses independent of BRCA1 or BRCA2 mutation (BRCAm) status. We therefore investigated this combination in the AMTEC clinical trial, in which a one-month olaparib run-in was followed by combined olaparib and durvalumab in participants with non-BRCAm metastatic triple negative breast cancer. To characterize adaptive responses to olaparib monotherapy, paire...

Since the first report of V (D) J " allelic exclusion/inclusion"and" dual BCR "in 1961, despite continuous new discoveries, the proportion and source mechanism of dual BCR under physiological conditions have been puzzling immuologists.This study takes advantage of the single cell V (D) J sequencing technology, which can perfectly match the heavy and light chains of BCR at the level of a single B cell, and obtain the full length mRNA sequence of the CDR3 region. By analyzing the pairing of functi...

Due to their genetic instability, tumor cells bear mutations that can effectively be recognized by the immune system. In the clinic, immune checkpoint immunotherapy (ICI) can re-activate immune reactions against mutated proteins, known as neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness remain elusive yet are needed to improve the success of cancer treatments. While th...

BackgroundPrecision radiation strategies that expand the therapeutic window by selectively sensitizing tumors and sparing normal tissues are needed. We developed a matched tumoroid-organoid preclinical platform to identify and characterize personalized radiosensitization strategies. MethodsWe established 15 rectal cancer-derived tumoroids and 3 matched normal rectal epithelial organoids. Whole exome sequencing characterized mutation profiles and phylogenetic relationships. Tumoroids were treate...

DARPins (Designed Ankyrin Repeat Proteins) are a non-antibody based protein scaffold which has undergone extensive clinical characterization. DARPins are small, stable proteins derived from naturally occurring ankyrin repeat proteins and are characterized by high binding affinity and specificity, and a flexible architecture enabling multispecific approaches beyond bi-specific molecules. A total of seven clinical DARPin drug candidates across therapeutic areas spanning ophthalmology (abicipar), v...

CAR T therapy for solid tumors is limited by a lack of safe and uniformly expressed cell-surface targets. Here, we identify the MiT fusion-driven protein GPNMB as being highly, homogeneously, and stably expressed in primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma (tRCC). We developed a GPNMB-targeting CAR T therapy called GCAR1 that shows activity against patient-matched cells, organoids and xenograft models. First-in-human treatment of a pa...

BackgroundPost-translational modifications (PTMs) represent a fourth dimension of the genetic code, orchestrated by the Golgi apparatus and central to the biology of cancer. The prevailing paradigm of oncofetal reprogramming posits that cancer cells reactivate embryonic developmental programs to drive tumorigenesis; however, the lineage-specific nature of this reversion remains incompletely defined. This review advances and systematically evaluates the hypothesis that the cancer PTM landscape is...

Polo-Like Kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a novel hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a new HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response elemen...

Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without other hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of breast cancer patients and showed that cytotoxic treatments (chemotherapy {+/-} radi...

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Whether treatment order--primary debulking surgery followed by adjuvant chemotherapy (PDS) or neo-adjuvant chemotherapy with interval surgery (NACT)--affects outcome is controversial. We developed a mathematical framework that holds for hierarchical or stochastic models of tumor initiation and reproduces HGSC clinical course. After estimating parameter values, we infer that most patients harbor chemo-resist...

This study identifies a novel pathotype of cervical cancer-associated Lactobacillus iners (L. iners) that results in chemoradiation resistance in vitro and is associated with poor patient survival. Cervical cancer affects over half a million women a year around the world. Treatment for women with locally advanced cancer is delivered with definitive chemoradiation (CRT) but is curative for only 60% of patients. There are few validated molecular markers to identify patients who will respond poorly...

Significant heterogeneity exists within the tumor infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted but activated (Tex/act) subpopulations critical to the improvement of therapeutic approaches. To investigate mechan...

Cancer cells invoke phenotypic plasticity programs to drive disease progression and evade chemotherapeutic insults, yet until now there have been no validated clinical therapies targeting this process. Here, we identify a phenotypic plasticity signature associated with poor survival in basal/triple-negative breast cancer, in which androgen signalling is prominent. We establish that anti-androgen therapies block cancer stem cell function and prevent chemotherapy-induced emergence of new cancer st...

BackgroundThe classical "seed and soil" hypothesis suggests that metastatic spread is shaped by tumor-intrinsic traits ("seeds") and the organ-specific microenvironment ("soil"). We expand this concept to explain lesion-level therapeutic responses and phenotypic variability across metastatic cancers. MethodsWe analyzed 55,220 lesions from 6,087 patients enrolled in 20 clinical trials across six cancer types. Using nonlinear mixed-effects modeling, we estimated lesion-specific parameters: regres...

Abstract/IntroductionA wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafolli...

A dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1highCXCR5-CD4+ T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory ...