Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that ...glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic “regressor” tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.
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•Tumor cells and TILs compete for glucose within the tumor niche•Metabolic competition can drive cancer progression•Checkpoint blockade antibodies alter the metabolic balance in a tumor•PD-L1 promotes Akt/mTOR activation and glycolysis in tumor cells
Glucose consumption by antigenic tumors can metabolically restrict T cells, directly dampening their effector function and allowing tumor progression. Checkpoint blockade therapy may correct this resource imbalance through a direct effect in the tumor cells.
Although current immune-checkpoint therapy (ICT) mainly targets lymphoid cells, it is associated with a broader remodeling of the tumor micro-environment. Here, using complementary forms of ...high-dimensional profiling, we define differences across all hematopoietic cells from syngeneic mouse tumors during unrestrained tumor growth or effective ICT. Unbiased assessment of gene expression of tumor-infiltrating cells by single-cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages, distinguishable by the markers CD206, CX3CR1, CD1d, and iNOS, that change over time during ICT in a manner partially dependent on IFNγ. Our data support the hypothesis that this macrophage polarization/activation results from effects on circulatory monocytes and early macrophages entering tumors, rather than on pre-polarized mature intratumoral macrophages.
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•High-dimensional analyses of successful ICT in tumor-bearing mice•ICT induces changes in intratumoral myeloid and lymphoid cells•Tumor-associated monocytes/macrophages display complex cytokine-driven phenotypes•Different cytokines act on tumor-infiltrating monocytes to drive macrophage polarization
Comprehensive changes in the tumor microenvironment during successful immune-checkpoint therapy are profiled, implicating a key role for polarization of infiltrating macrophages in the anti-tumor immune milieu.
Although thymic carcinoma is a rare epithelial neoplasm that tends to be aggressive and metastasize widely, its incidence in Japan remains unclear. This study was to examine the incidence and initial ...treatment of thymic carcinoma in the Japanese population using data from a hospital-based cancer registry.
Using data from the national database of hospital-based cancer registries, we examined the incidence and initial treatment of thymic carcinoma diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. Based on Japanese population estimates, we calculated the incidence rate of thymic cancer in Japan.
A total of 2587 thymic carcinoma cases were diagnosed between 1 January 2009 and 31 December 2015. These patients consisted of 1705 (66%) men and 882 (34%) women, with a median age of 65.5 years (range, 16-96 years). The number and proportion of thymic carcinoma to all registered cancer cases per year increased each year. The incidence rate was estimated to be 0.29/100000 during the observation period, with an annual onset incidence of 0.38/100000 in 2015. Almost half of all cases of thymic carcinoma were treated surgically, while the others were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy.
We estimated the incidence rate of thymic carcinoma in Japan based on the designated cancer care hospital-based cancer registry. The half of all patients with thymic carcinoma was unfit for multimodality therapy, including thoracic surgery.
Osimertinib is a third‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR‐mutated non–small‐cell lung ...cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug‐tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non‐genetic acquired resistance to EGFR‐TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous‐generation EGFR‐TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ‐secretase inhibitor (GSI), a Notch inhibitor, impairs drug‐tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho‐ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR‐TKI treatment in half of human EGFR‐mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR‐mutated NSCLC.
The Notch pathway is activated in osimertinib drug‐tolerant persister cells and might be targeted for EGFR‐mutated patients in their osimertinib treatment.
Tumor cells in extramammary Paget's disease sometimes overexpress human epidermal growth factor receptor 2 (HER2). Several case reports indicated successful response to HER2 inhibitor in patients ...with HER2-positive metastatic extramammary Paget's disease. However, these were single-case reports, and most cases were evaluated only by immunohistochemistry and treated with HER2 inhibitor monotherapy. Here, we report cases of HER2-positive metastatic extramammary Paget's disease identified by both immunohistochemistry and in situ hybridization, and the patients were treated with HER2 inhibitor (trastuzumab) and paclitaxel combination chemotherapy. Partial response was observed in one case. The case was positive on both immunohistochemistry (3+) and in situ hybridization (HER2/chromosome 17 centromere, ≥2.0). Our observations suggest that HER2 should be checked in patients with advanced and/or metastatic extramammary Paget's disease, and that therapy with HER2 blockers should be considered as an option for treatment of HER2-positive extramammary Paget's disease, especially in cases positive for both HER2 gene amplification and overexpression.
Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR‐mutant non–small‐cell lung cancer (NSCLC) cells. However, little is known about the ...mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR‐mutant cells. Using EGFR‐mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR‐TKI treatment, we found that EGFR‐mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first‐generation EGFR‐TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre‐treatment samples. Monocyte‐derived macrophages facilitated antibody‐dependent cellular phagocytosis when EGFR‐TKI‐treated EGFR‐mutant cells were incubated with anti‐CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR‐mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell‐free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP‐1 monocytes in a stimulator of interferon genes‐dependent manner. Our study indicates that EGFR inhibition in EGFR‐mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR‐mutant NSCLC.
EGFR inhibition in EGFR‐mutant lung cancer cells results in the upregulation of tumor CD24. It also accelerates the release of tumor‐derived cell‐free DNA, triggering the type I interferon pathways. These biomarkers are potential targets to overcome the resistance to EGFR‐targeted therapy.
Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine ...whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance.
Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m
) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients.
CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake.
ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.
Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens ...and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.
BackgroundImmune checkpoint blockade (ICB) has been shown to elicit long-term, durable responses in patients with metastatic or unresectable lung cancer. Similar to immunity against pathogens, ...memory-like antitumor T cell response may be pivotal in these patients. Nonetheless, due to the absence of suitable clinic-to-bench preclinical animal models, the mechanisms behind the generation of beneficial T cells following ICB in lung cancer remain largely unexplored.MethodsSubclones were obtained from a syngeneic murine lung cancer cell line. Alongside confirming their genomic oncogenicity through whole exome sequencing, MHC class I and class II neoantigens within the subclones were computationally identified. The subclones were subsequently tested in vivo for their sensitivity to ICB, including anti-PD-1 monotherapy and a combination of anti-PD-1 and anti-CTLA-4, both of which are the standard of care for lung cancer. Additionally, we assessed the role of memory-like antitumor T cell response in wild-type and Batf3 knockout (KO) mice that had previously rejected the lung tumor cells post-ICB treatment.ResultsThree subclones, huL1, huL2, and huL3, were established. These retained oncogenic driver mutations, such as Kras, Nras, and Trp53, present in the parental cells, and also shared immunogenic MHC class I and class II neoantigens. Wild-type mice were subcutaneously challenged with 1x106 tumor cells, followed by ICB treatment on days 3, 6, and 9. Upon anti-PD-1 monotherapy, tumor rejection rates in mice bearing huL1, huL2, and huL3 were 30%, 0%, and 50%, respectively. Treatment with a combination of anti-PD-1 and anti-CTLA-4 improved rejection rates to 20% for huL1, 36% for huL2, and 100% for huL3. Following a minimum interval of three weeks after the rejection of huL3 tumors, mice were re-challenged with 5x106 huL3 tumor cells on the opposite flank. Despite remaining untreated, these mice spontaneously rejected the secondary-challenged tumor cells. The same approach was replicated with Batf3 KO mice, which also rejected huL3 tumor cells when treated with the ICB combination, albeit at a rate of 50%. Interestingly, these tumor-free Batf3 KO mice could not spontaneously reject re-challenged huL3 tumor cells, unlike their wild-type counterparts.ConclusionsWe have developed a novel preclinical lung cancer model that assesses antitumor immunological memory through tumor rejection. Our research findings suggest that Batf3 is crucial for the development of memory-like antitumor T cells following ICB.
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