Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.
Tsoi et al. show that melanoma can be categorized into four subtypes following a differentiation trajectory with subtype-specific sensitivity to ferroptosis induction, which presents a therapeutic approach to target the differentiation plasticity to increase the efficacy of targeted and immune therapies.
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Here, we present a review of recent discoveries in the field of platelet biology and the role of platelets in cancer progression as well as challenges in targeting platelets for cancer treatment.
Revisiting the role of ABC transporters in multidrug-resistant cancer
Revisiting the role of ABC transporters in multidrug-resistant cancer, Published online: 11 April 2018; doi:10.1038/s41568-018-0005-8
This Opinion argues for a new look at the role of ABC transporters in cancer multidrug resistance to push forward their clinical application as biomarkers and as targets in combination therapies in order to improve anticancer drug efficiency.
(Cancer Cell 33, 29–43; January 8, 2018)
Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. In this issue of Cancer Cell, two articles by Stammnitz et al. and Frampton et al. present novel insights into the potential mechanisms underlying the propagation of naturally occurring transmissible cancers in mammals.
Understanding how agonistic and checkpoint control antibodies mediate their activity in vivo is essential for further development of these promising anti-cancer therapies. In this issue of Cancer Cell, studies by Vargas et al. and Yu et al. provide insights into the mode of action of CTLA-4- and CD40-specific antibodies.
The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.
Stammnitz et al. show that the two transmissible cancer clones that affect Tasmanian devils are very similar in their tissues-of-origin, mutational patterns and driver gene candidates. Importantly, these cancers are both highly sensitive to inhibitors of some receptor tyrosine kinases as well as to inhibitors of DNA repair.
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
Selective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens.
(Cancer Cell 33, 322–336; February 12, 2018)
Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.
Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Here, we review functional roles of immune checkpoints and molecular determinants of checkpoint-blockade clinical activity. Limited-size T cell-infiltrated tumors, differing substantially from “self,” generally respond to checkpoint blockade. Therefore, we propose that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy. Lastly, we outline criteria to select proper immunotherapy combination partners and highlight the importance of activity biomarkers for timely treatment optimization.
By analyzing serial biopsies of vincristine-treated canine transmissible venereal tumors, Frampton et al. show that tumor regression occurs in sequential steps involving the activation of the innate immune system and immune infiltration of the tumor, and they identify CCL5 as a possible driver of regression.
Huang et al. show in a prostate cancer mouse model that p62 loss in adipocytes leads to aggressive disease by increasing osteopontin secretion, which mediates tumor fatty acid oxidation and invasion. P62 deficiency also represses energy-consuming pathways in adipocytes, increasing nutrient availability for tumors.
Too many targets, not enough patients: rethinking neuroblastoma clinical trials
Too many targets, not enough patients: rethinking neuroblastoma clinical trials, Published online: 09 April 2018; doi:10.1038/s41568-018-0003-x
This Perspective provides an update on targeted therapy development for neuroblastoma and proposes that clinical trial design needs to be rethought in order to provide rigorous, evidence-based assessment of these new therapies in this rare and often deadly paediatric tumour.
Breast cancer: Obesity — tipping the scales of resistance
Breast cancer: Obesity — tipping the scales of resistance, Published online: 06 April 2018; doi:10.1038/nrc.2018.31
Using clinical tissue specimens and mouse models of breast cancer, Incio et al. show that obesity promotes the upregulation of interleukin-6 and fibroblast growth factor 2 in the tumour microenvironment, which confer resistance to anti-vascular endothelial growth factor therapy.
Mechanisms of cancer resistance in long-lived mammals
Mechanisms of cancer resistance in long-lived mammals, Published online: 05 April 2018; doi:10.1038/s41568-018-0004-9
In this Opinion article, Seluanov et al. discuss the diverse mechanisms of cancer resistance found in long-lived mammals and argue that studies of unconventional long-lived and cancer-resistant animal species could provide breakthroughs in cancer therapy and prevention.