PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.

A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/ß, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in patients with cancer. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses.

A novel liver-function-indicators-based prognosis signature for patients with hepatocellular carcinoma treated with anti-programmed cell death-1 therapy.

BACKGROUND: The liver function reserve has a significant impact on the therapeutic effects of anti-programmed cell death-1 (PD-1) for hepatocellular carcinoma (HCC). This study aimed to comprehensively evaluate the ability of liver-function-based indicators to predict prognosis and construct a novel prognostic score for HCC patients with anti-PD-1 immunotherapy. METHODS: Between July 2018 and January 2020, patients diagnosed with HCC who received anti-PD-1 treatment were screened for inclusion in the study. The valuable prognostic liver-function-based indicators were selected using Cox proportional hazards regression analysis to build a novel liver-function-indicators-based signature (LFIS). Concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and Kaplan-Meier survival curves were utilized to access the predictive performance of LFIS. RESULTS: A total of 434 HCC patients who received anti-PD-1 treatment were included in the study. The LFIS, based on alkaline phosphatase-to-albumin ratio index, Child-Pugh score, platelet-albumin score, aspartate aminotransferase-to-lymphocyte ratio index, and gamma-glutamyl transpeptidase-to-lymphocyte ratio index, was constructed and identified as an independent risk factor for patient survival. The C-index of LFIS for overall survival (OS) was 0.692, which was higher than the other single liver-function-based indicator. The AUC of LFIS at 6-, 12-, 18-, and 24-month were 0.74, 0.714, 0.747, and 0.865 for OS, respectively. Patients in the higher-risk LFIS group were associated with both worse OS and PFS. An online and easy-to-use calculator was further constructed for better application of the LFIS signature. CONCLUSION: The LFIS score had an excellent prognosis prediction ability superior to every single liver-function-based indicator for anti-PD-1 treatment in HCC patients. It is a reliable, easy-to-use tool to stratify risk for OS and PFS in HCC patients who received anti-PD-1 treatment.

Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer patients.

The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.

Impact of preoperative antiviral therapy on the prognosis of hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. METHODS: 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People's Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. RESULTS: NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA < 1000 copy/mL had significantly better recurrence-free survival (RFS) and OS than those with HBV DNA ≥ 1000 copy/mL (HR: 7.783; P = 0.002; HR: 6.699; P < 0.001). However, the differences of RFS and OS rates between entecavir group and tenofovir disoproxil fumarate group were not statistically significant. Similar results were also observed in the rates of early VR, BR and combined VR and BR. CONCLUSION: Timely and reasonable preoperative NAs therapy showed clinical benefit in improving the prognosis of patients with HBV-related HCC, even in the case of normal alanine aminotransferase (ALT) level and negative hepatitis e antigen (HBeAg). Furthermore, a possible synergistic effect between antiviral therapy and anti-PD-1 therapy was founded and need further verification.

NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.

CSF1R inhibition reprograms tumor-associated macrophages to potentiate anti-PD-1 therapy efficacy against colorectal cancer.

PD-1 blockade therapy has made great breakthroughs in treatment of multiple solid tumors. However, patients with microsatellite-stable (MSS) colorectal cancer (CRC) respond poorly to anti-PD-1 immunotherapy. Although CRC patients with microstatellite instability (MSI) or microsatellite instability-high (MSI-H) can benefit from PD-1 blockade therapy, there are still some problems such as tumor recurrence. Tumor-associated macrophages (TAMs), most abundant immune components in tumor microenvironment (TME), largely limit the therapeutic efficacy of anti-PD-1 against CRC. The CSF1/CSF1R pathway plays a key role in regulating macrophage polarization, and blocking CSF1R signaling transduction may be a potential strategy to effectively reprogram macrophages and remodel TME. Here, we found that increasing expression of CSF1R in macrophages predicted poor prognosis in CRC cohort. Furthermore, we discovered a novel potent CSF1R inhibitor, PXB17, which significantly reprogramed M2 macrophages to M1 phenotype. Mechanically, PXB17 significantly blocked activation of PI3K/AKT/mTORC1 signaling, resulting in inhibition of cholesterol biosynthesis. Results from 3D co-culture system suggested that PXB17-repolarized macrophages could induce infiltration of CD8+ T lymphocytes in tumors and improve the immunosuppressive microenvironment. In vivo, PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC.

Dynamic changes in peripheral blood monocytes early after anti-PD-1 therapy predict clinical outcomes in hepatocellular carcinoma.

Immune checkpoint inhibitors are effective for advanced hepatocellular carcinoma (HCC), but there remains a need for peripheral blood biomarkers to predict the clinical response. Here, we analyzed the peripheral blood of 45 patients with advanced HCC who underwent nivolumab. During treatment, frequency of classical monocytes (CD14+CD16-) was increased on day 7, and the fold increase in the frequency on day 7 over day 0 (cMonocyteD7/D0) was significantly higher in patients with durable clinical benefit (DCB) than in patients with non-DCB (NDB). When we analyzed transcriptomes of classical monocytes, CD274, gene encoding PD-L1, was upregulated in NDB patients compared to DCB patients at day 7. Notably, gene signature of suppressive tumor-associated macrophages, or IL4l1+PD-L1+IDO1+ macrophages, was enriched after treatment in NDB patients, but not in DCB patients. Accordingly, the fold increase in the frequency of PD-L1+ classical monocytes at day 7 over day 0 (cMonocyte-PDL1D7/D0) was higher in NDB patients than DCB patients. The combined biomarker cMonocyteD7/D0/cMonocyte-PDL1D7/D0 was termed the "monocyte index", which was significantly higher in DCB patients than NDB patients. Moreover, the monocyte index was an independent prognostic factor for survival. Overall, our results suggest that early changes of circulating classical monocytes, represented as a monocyte index, could predict clinical outcomes of advanced HCC patients undergoing anti-PD-1 therapy.

Nomogram for predicting the prognosis of metastatic colorectal cancer patients treated with anti-PD1 therapy based on serum lipids analysis.

BACKGROUND: Serum lipids have been identified to be used as prognostic biomarkers in several types of cancer. The primary objective of this study was to evaluate the prognostic value of serum lipids in metastatic colorectal cancer (mCRC) patients received anti-PD-1 therapy. METHODS: Pretreatment and the alteration of serum lipids, including apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) after 2 courses of anti-PD1 therapy, were collected. Kaplan-Meier survival and cox regression analysis were performed to identify the prognostic values on overall survival (OS). Finally, those significant predictors from multivariate analysis were used to construct a nomogram for the prediction of prognosis. RESULTS: Baseline ApoB, CHO, HDL-C, LDL-C and early changes of ApoB, ApoA-I, HDL-C were statistically significant in the ROC analysis, showing good discriminatory ability in terms of OS. In multivariate analysis, treatment lines, lung metastasis, baseline HDL-C (low vs. high, HR, 6.30; 95% CI 1.82-21.80; P = 0.004) and early changes in HDL-C (reduction vs. elevation, HR, 4.59, 95% CI 1.20-17.63; P = 0.026) independently predicted OS. The area under the time-dependent ROC curve at 1 year, 2 years and 3 years consistently demonstrated the satisfactory accuracy and predictive value of the nomogram (AUC: 0.88, 0.85, 0.84). CONCLUSION: Overall, high level at baseline and an early elevation of HDL-C are correlated with better outcomes in mCRC patients treated with anti-PD1 therapy. The constructed nomogram indicated that the factors are strong predictive markers for response and prognosis to anti-PD-1 therapy in metastatic colorectal cancer.

Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy.

BACKGROUND: The efficacy of current immunotherapeutic strategies for patients with glioblastoma multiforme (GBM) remains unsatisfactory. The purpose of this study was to investigate the correlation between tumor necrosis factor alpha-induced protein 2 (TNFAIP2) and immunogenic cell death (ICD) in GBM, and to examine the effect of TNFAIP2 knockdown and anti-PD-1 combination treatment in a mouse glioma model. METHODS: The CGGA and TCGA databases were used to explore the possible function of TNFAIP2 in GBM. Multiplex immunohistochemistry (mIHC) staining was performed to detect the immune infiltration of tissues. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and enzyme linked immunosorbent assay (ELISA) were utilized to detect the release of damage-associated molecular patterns (DAMPs) and the activation of the immune response. A mouse glioma model was applied to examine the induction of immune response. RESULTS: In vitro and in vivo studies demonstrated that TNFAIP2 knockdown increased the surface exposure of calreticulin (CALR), heat shock protein 70 kDa (HSP70), and heat shock protein 90 kDa (HSP90) in GBM cell lines, thereby inducing immunogenic cell death (ICD). Importantly, the study found that TNFAIP2 knockdown in combination with anti-PD-1 therapy significantly improved the overall survival of glioma in a mouse model. CONCLUSIONS: TNFAIP2 knockdown induces ICD by downregulating TNFAIP2 in GBM. In addition, TNFAIP2 knockdown sensitized glioma to anti-PD-1 therapy. Hence, targeting TNFAIP2 alone or in combination with anti-PD-1 therapy may be a potential strategy for GBM treatment through ICD.

Structure of PD1 and its mechanism in the treatment of autoimmune diseases.

PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

BACKGROUND: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear. RESULTS: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb). CONCLUSIONS: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

Rhamnazin Enhanced Anti-Tumor Efficacy of Anti-PD-1 Therapy for Lung Cancer in Mice through Inhibition of PD-L1 Expression.

Emerging studies suggest the significance of broadening the benefit of anti-programmed cell death 1 (PD-1) therapy for lung cancer. The anti-angiogenic agents have been reported to alter the tumor microenvironment and contributes to efficiency of anti-PD-1 therapy. This study aims to investigate whether the anti-angiogenic agent rhamnazin enhances the efficacy of anti-PD-1 therapy in lung cancer. In Lewis lung carcinoma (LLC) xenografts, the combination of rhamnazin and anti-PD-1 treatment suppressed tumor growth, elevated the infiltration of CD4+ T and CD8+ T cells in tumors and up-regulated interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and granzyme B. Furthermore, the combination reduced programmed cell death ligand 1 (PD-L1) expression in tumors more significant than anti-PD-1 treated group. In LLC cell experiments, rhamnazin inhibited vascular endothelial growth factor A (VEGFA)-stimulated vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation and PD-L1 expression, whereas VEGFR2 overexpression reversed these trends. T cell proliferation and cytotoxic factor production were evaluated after co-culturing with non-small cell lung cancer (NSCLC) H1975 cells. Rhamnazin promotes T cell proliferation and up-regulated IFN-γ, TNF-α and granzyme B in the co-culture system, while VEGFR2 overexpression abrogated these changes. These data suggest that rhamnazin enhances anti-tumor effect of anti-PD-1 therapy for lung cancer in mice via inhibition of PD-L1 expression.

[Gastric cancer with impaired DNA unpaired nucleotide repair system]. / Rak zheludka s narusheniem sistemy reparatsii nesparennykh nukleotidov DNK.

This article presents a case of successful treatment of inoperable gastric cancer with impaired mismatched nucleotide repair system (dMMR/MSI-H) in a 72-year-old patient. In view of age, somatic status and the presence of comorbidity, it was decided to prescribe anti-PD-1 therapy in the 1st line of treatment. Currently, after a 2-year course of treatment, the patient is in stable remission.

FDG-PET to predict long-term outcome from anti-PD-1 therapy in metastatic melanoma.

BACKGROUND: We have previously shown that 75% of patients treated with programmed cell death protein 1 (PD-1) with or without CTLA4 who have not progressed by 1 year have complete metabolic response (CMR), including two-thirds of patients with partial response (PR). We now report 5-year outcomes. PATIENTS AND METHODS: Retrospective analysis of 104 patients with baseline and 1-year positron emission tomography (PET) and computed tomography (CT). The 1-year response was determined using RECIST for CT and European Organisation for Research and Treatment of Cancer (EORTC) criteria for PET. Progression-free survival (PFS) and overall survival (OS) were determined from the 1-year landmark. RESULTS: At the median follow-up of 61 months (range 58-64 months) from 1-year PET, 94% remained alive and all but one had discontinued treatment after a median treatment duration of 23 months (range 1-59 months). Disease progression occurred in 19 patients (18%): 10 (53%) while on treatment and 12 (63%) in solitary sites for which 8 (67%) received local treatment. RECIST PFS rate at 5 years after PET was higher in complete response (CR) compared with PR/stable disease (SD) (93% versus 76%, respectively) and CMR compared with non-CMR (90% versus 54%, respectively). In patients with PR, 5-year PFS rate was superior in CMR (88% and 59%). A total of 35 (34%) patients (14/29 in CR, 31/78 in CMR) discontinued treatment within 12 months, largely due to toxicity, with no impact on PFS rate compared with those that continued (84% versus 78%). Despite progression events, OS rate at 5 years was excellent and similar in patients with CR and PR/SD (100% versus 91%, respectively) as well as in those with CMR and non-CMR (96% versus 87%, respectively). CONCLUSIONS: Five years after the 1-year PET, sustained responses are observed in the majority of patients, particularly in those with CMR. PET continues to predict progression better than CT, particularly in those with residual disease on CT. In the minority that progress, often in solitary sites and managed locally, OS rate remains excellent. PET is effective in evaluating residual lesions on CT and can predict long-term benefit.

Anti-PD1/PDL1 IgG subclass distribution in ten cancer types and anti-PD1 IgG4 as biomarker for the long time survival in NSCLC with anti-PD1 therapy.

BACKGROUND: Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy. METHOD: Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32). RESULTS: Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS, p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032). CONCLUSION: This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.

Redistribution of CD8+ T cell subsets in metastatic renal cell carcinoma patients treated with anti-PD-1 therapy.

Renal-cell carcinoma (RCC) is responsible for the majority of tumors arising from the kidney parenchyma. Although a progressive improvement in median overall survival has been observed after the introduction of anti-PD-1 therapy, many patients do not benefit from this treatment. Therefore, we have investigated T cell dynamics to find immune modification induced by anti-PD-1 therapy. Here, we show that, after therapy, RCC patients (5 responders and 14 nonresponders) are characterized by a redistribution of different subsets across the memory T cell compartment.

Real-world outcomes in patients with first-line and second-line therapy for advanced esophageal squamous cell carcinoma.

Background: Little is known about real-world outcomes for first-line and anti-PD-1 second-line treatment for advanced/metastatic esophageal squamous cell carcinoma (ESCC). Patients & methods: Retrospective data of advanced/metastatic ESCC patients treated between 2011 and 2021 were collected from Flatiron Health. Median duration of therapy (mDoT) and median overall survival (mOS) were evaluated for patients initiating first-line and anti-PD-1 second-line therapy. Results: Among patients receiving first-line therapy (n = 948), mDoT was 1.4 months and mOS was 16.0 months, with mOS of 16.0 and 18.0 months for the non-immunotherapy and immunotherapy cohorts, respectively. Among patients receiving anti-PD-1 second-line therapy (n = 60), mDoT was 5.7 months and mOS was 10.1 months. Conclusion: Patients with advanced/metastatic ESCC have short duration of therapy, and overall survival remains limited. This real-world study underscores the need for efficacious treatments for advanced/metastatic ESCC in the first- and second-line setting. Direct comparisons of emerging therapies in the real world are urgently needed.

Tumor Treating Fields (TTFields) Concomitant with Immune Checkpoint Inhibitors Are Therapeutically Effective in Non-Small Cell Lung Cancer (NSCLC) In Vivo Model.

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields induce anti-mitotic effects through the disruption of the mitotic spindle and abnormal chromosome segregation, which trigger several forms of cell death, including immunogenic cell death (ICD). The efficacy of TTFields concomitant with anti-programmed death-1 (anti-PD-1) treatment was previously shown in vivo and is currently under clinical investigation. Here, the potential of TTFields concomitant with anti- PD-1/anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed death-ligand 1 (anti-PD-L1) immune checkpoint inhibitors (ICI) to improve therapeutic efficacy was examined in lung tumor-bearing mice. Increased circulating levels of high mobility group box 1 protein (HMGB1) and elevated intratumoral levels of phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α) were found in the TTFields-treated mice, indicative of ICD induction. The concomitant application of TTFields and ICI led to a significant decrease in tumor volume as compared to all other groups. In addition, significant increases in the number of tumor-infiltrating immune cells, specifically cytotoxic T-cells, were observed in the TTFields plus anti-PD-1/anti-CTLA-4 or anti-PD-L1 groups. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production. Collectively, these results suggest that TTFields have an immunoactivating role that may be leveraged for concomitant treatment with ICI to achieve better tumor control by enhancing antitumor immunity.

High tumor mutational burden and T-cell activation are associated with long-term response to anti-PD1 therapy in Lynch syndrome recurrent glioblastoma patient.

BACKGROUND: Glioblastomas (GBMs) in patients harboring somatic or germinal mutations of mismatch-repair (MMR) genes exhibit a hypermutable phenotype. Here, we describe a GBM patient with increased tumor mutational burden and germline MMR mutations, treated using anti-PD1 therapy. METHODS: A woman with newly diagnosed GBM (nGBM) was treated by surgery, radiotherapy, and temozolomide. The tumor recurred after 13 months leading to a second surgery and treatment with nivolumab. Whole-exome sequencing was performed on the nGBM, recurrent GBM (rGBM), and blood. Immune infiltration was investigated by immunohistochemistry and the immune response in the blood during treatment was analyzed by flow cytometry. RESULTS: High density of infiltrating CD163 + cells was found in both GBM specimens. Large numbers of CD3 + and CD8 + T cells were homogeneously distributed in the nGBM. The infiltration of CD4 + T cells and a different CD8 + T cell density were observed in the rGBM. Both GBM shared 12,431 somatic mutations, with 113 substitutions specific to the nGBM and 1,683 specific to the rGBM. Germline variants included pathogenic mutation in the MSH2 (R359S) gene, suggesting the diagnosis of Lynch syndrome. Systemic immunophenotyping revealed the generation of CD8 + T memory cells and persistent activation of CD4 + T cells. The patient is still receiving nivolumab 68 months after the second surgery. CONCLUSIONS: Our observations indicate that the hypermutator phenotype associated with germinal mutations of MMR genes and abundant T-cell infiltration contributes to a durable clinical benefit sustained by a persistent and robust immune response during anti-PD1 therapy.