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Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R 2  = 0.87, p  < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies. The detection of aberrations in circulating tumour DNA represents a non-invasive method to survey the oncogenes and tumour suppressors that are modified within a patient’s cancer. Here, the authors analysed more than 10,000 patients using a targeted sequencing panel and report on the frequencies of the mutations that they found.

Although a role of PD-L1 in the suppression of anti-tumor immunity and its value as a predictive biomarker has been suggested by various preclinical and clinical studies, the precise mechanisms how PD-L1 and PD-L2, another ligand of PD-1, regulate anti-tumor immunity in the tumor microenvironment are yet to be fully explored. Here, we address this issue using PD-L1-deficient tumor cells, PD-L1-knockout (KO) mice, anti-PD-L1 monoclonal antibody (mAb), and anti-PD-L2 mAb. Firstly, PD-L1-deficient or competent tumor cells were inoculated into wild-type or PD-L1-KO mice. Results of tumor growth and mouse survival indicated that both tumor- and host-derived PD-L1 are functional to suppress anti-tumor immunity, while the former contributes predominantly than the latter. Experiments using bone marrow (BM) chimeric mice, generated by transferring PD-L1-KO BM cells into wild-type mice or vice versa, further suggested that PD-L1 expressed on BM-derived hematopoietic cells mediates the suppressive effects on anti-tumor immunity. Secondly, anti-PD-L2 mAb treatment demonstrated a profound synergy with anti-PD-L1 mAb therapy, whereas anti-PD-L2 mAb alone hardly induced any anti-tumor effects, suggesting that PD-L2’s function becomes evident when the effects of PD-L1 are abrogated by anti-PD-L1 mAb. Consistent with this notion, PD-L2 expression was upregulated on tumor-associated macrophages (TAM) when mice were treated with anti-PD-L1 mAb. Taken together, our study elucidated the importance of PD-L1 associated with tumor cells and non-tumor host cells, particularly BM-derived hematopoietic cells, as well as PD-L2 inducibly expressed on TAM in the suppression of anti-tumor immunity in the tumor microenvironment.

Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >10(5) parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. (13)C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB. Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8 + T cells 1 – 3 . Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name ‘mature DCs enriched in immunoregulatory molecules’ (mregDCs), owing to their coexpression of immunoregulatory genes ( Cd274 , Pdcd1lg2 and Cd200 ) and maturation genes ( C d40 , C cr7 and Il12b ). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein—a key checkpoint molecule—in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers. After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.

Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.

A selective class IIa histone deacetylase inhibitor induces anti-tumour immunity in a mouse model of mammary cancer through altered differentiation and recruitment of tumour-associated macrophages. Using anti-tumour macrophages in breast cancer Tumour-associated macrophages often benefit tumours, but previous efforts to either deplete or stimulate them have had some anti-tumour effects. Anthony Letai and colleagues suggest that using drugs to modify their phenotype could be even more successful. They show that a class IIa histone deacetylase inhibitor, TMP195, induces anti-tumour immunity in a mouse model of breast cancer. Treatment is associated with altered differentiation and recruitment of tumour-associated macrophages, and acts synergistically with chemotherapy and T-cell checkpoint blockade. Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects 1 , but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) 2 , 3 or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) 4 , 5 tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro 6 . Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non‐small‐cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA‐4/PD‐1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log‐rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06‐0.50], P < .001). The association with progression‐free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD‐L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12‐0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non‐responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC. Multivariate analysis of APOBEC mutational signature is strongly associated with objective immune response and progression‐free survival in immunotherapy, but not identified in conventional chemotherapy of the Cancer Genome Atlas (TCGA) samples, suggesting the specific predictive effects of ICB treatment. High APOBEC mutational activity samples were enriched for immune checkpoint gene markers and tumor immune lymphocyte infiltration makers. Combined TMB with an APOBEC signature may preferably predict NSCLC immunotherapy responders. Individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, PTEN was only noticed in non‐responders.

Combinational administration of chemotherapy (CT) and photothermal therapy (PTT) has been widely used to treat cancer. However, the scheduling of CT and PTT and how it will affect the therapeutic efficacy has not been thoroughly investigated. The challenge is to realize the sequence control of these two therapeutic modes. Herein, we design a temperature sensitive upconversion nanocomposite for CT-PTT combination therapy. By monitoring the microscopic temperature of the nanocomposite with upconversion luminescence, photothermal effect can be adjusted to achieve thermally triggered combination therapy with a sequence of CT, followed by PTT. We find that CT administered before PTT results in better therapeutic effect than other administration sequences when the dosages of chemodrug and heat are kept at the same level. This work proposes a programmed method to arrange the process of combination cancer therapy, which takes full advantage of each therapeutic mode and contributes to the development of new cancer therapy strategies. The combination of chemo and photothermal therapy is widely used to treat cancer but control of chemo and thermal effects is needed for optimized treatment. Here, the authors describe an upconversion nanoparticle which can be used for controlled sequential treatment by controlling laser power.

The role and characteristics of tumor-associated neutrophils (TAN) in cancer are poorly defined. We have recently shown that TAN can have anti-tumorigenic (N1) or pro-tumorigenic (N2) functions. An interesting unanswered question is how the phenotype of TAN is influenced by the ongoing evolvement of tumor microenvironment. We therefore studied the phenotype and effects of TAN at different time points during tumor progression. We used two models of murine tumor cancer cell lines—Lewis lung carcinoma (LLC) and AB12 (mesothelioma). Neutrophils were studied at early and late stages and compared to each other and to neutrophils from bone marrow/periphery of naïve mice. Although there was no difference in the number of neutrophils entering the tumor, we found that at early stages of tumor development, neutrophils were almost exclusively at the periphery of the tumor. Only at later stages, neutrophils were also found scattered among the tumor cells. We further found that TAN from early tumors are more cytotoxic toward tumor cells and produce higher levels of TNF-α, NO and H 2 O 2 . In established tumors, these functions are down-regulated and TAN acquire a more pro-tumorigenic phenotype. In line with this phenotype, only depletion of neutrophils at later stages of tumor development inhibited tumor growth, possibly due to their central location in the tumor. Our work adds another important layer to the understanding of neutrophils in cancer by further characterizing the changes in TAN during time. Additional research on the functional role of TAN and differences between subsets of TAN is currently underway.