Personalized cancer immunotherapy targeting patient-specific cancer/testis antigens (CTA) and neoantigens may benefit from large-scale tumor human leukocyte antigen (HLA) peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. While significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This work attempted to overcome some of these obstacles by using patient-derived xenograft tumors (PDX) in mice as the tissue sources for HLA peptidome analysis. PDX tumors provide a proxy for the expansion of the patient tumor by re-grafting them through several passages to immune-compromised mice. The HLA peptidomes of human biopsies were compared to those derived from PDX tumors. Larger HLA peptidomes were obtained from the significantly larger PDX tumors as compared to the patient biopsies. The HLA peptidomes of different PDX tumors derived from the same source tumor biopsy were very reproducible, even following subsequent passages to new naïve mice. A large number of CTA-derived HLA peptides were discovered, as well as several potential neoantigens/variant sequences. Taken together, the use of PDX tumors for HLA peptidome analysis serves as a highly expandable and stable source of reproducible and authentic peptidomes, opening up new opportunities for defining large HLA peptidomes when only small tumor biopsies are available. This approach provides a large source for tumor antigens identification, potentially useful for personalized immunotherapy.
Background Different factors may lead to hepatitis. Among which are liver inflammation and poisoning. We chose two hepatitis models, typical for these two underlying causes. Thus, we aimed to characterize the role of protease-activated receptor 2 (Par2) in liver regeneration and inflammation to reconcile Par2 conflicting role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it. Methods WT and knockout (Par2KO) mice were injected with concanavalin A (ConA) to induce immune-mediated hepatitis or with carbon tetrachloride (CCl4) to elicit direct hepatic damage. To distinguish the immune component from the liver regenerative response, we conducted bone marrow (BM) replacements of WT and Par2KO mice and repeated the damage models. Results ConA injection caused limited damage in Par2KO mice livers, while in the WT mice severe damage followed by leukocyte infiltration was evident. Reciprocal BM replacement of WT and Par2KO showed that WT BM-reconstituted Par2KO mice displayed marked liver damage, while in Par2KO BM-reconstituted WT mice, the tissue was generally protected. In the CCl4 direct damage model, hepatocytes regenerated in WT mice, whereas Par2KO mice failed to recover. Reciprocal BM replacement did not show significant differences in hepatic regeneration. In Par2KO mice, hepatitis was more apparent, while WT recovered regardless of the BM origin. Conclusions We conclude that Par2 activation in the immune system aggravates hepatitis and that Par2 activation in the damaged tissue promotes liver regeneration. When we incorporate this finding and revisit the literature reports, we reconciled the conflicts surrounding Par2’s role in injury, recovery, and inflammation.
Background: Circulating tumor cells (CTCs) originate from both primary and metastatic solid tumors and infiltrate the blood system. Although the metastatic potential of the single CTC cell is unknown, CTCs in circulation have been reported to have prognostic value as early predictors of relapse in cancers including ovarian, breast, colorectal, prostate, lung, bladder, head and neck and melanoma. As metastatic spread remains the major problem in cancer treatment, it is of great importance to characterize the subpopulations of CTCs with the highest metastatic potential. Methods: Peripheral blood mononuclear cells (MNCs) or bone marrow MNCs, were collected from each of over 60 cancer patients and grafted separately to immunodeficient NOD.Cg-Prkdc.scid.Il2rgtm1Wjl/SzJ (NSG) mice. Additionally, CTCs were enriched by either CD8 T-cell depletion or by a size-based filtration system. Tumors that developed in the mice were confirmed to be human tumors by demonstrating that they have human HLA expression and by comparing their tumor type by an independent pathologist to that of the donor patient's. The CTC-derived tumors were passaged to naive NSG mice to establish the scale up potential for treatment-groups. To facilitate future research of CTC-derived tumors, we have established a Biobank for CTC-derived tumors with matched samples of the patient's MNCs, plasma, tumor biopsy(s) and patient-biopsy derived xenograft (PDX) tumors. Additional characterization of the CTC-derived tumors was performed, such as comparison to the driver-mutations of the original tumor-biopsies and expression of epithelial or mesenchymal markers. The clinical relevance of the CTC-derived tumors was assessed by long term follow-up of each patient's disease progression. Results: CTC-derived tumors were detected in xenografts in 15 cases, within an average of eight months post grafting, representing a 25% success rate. The CTC-derived tumors were from a variety of cancers including: breast (6), colon (1), lung (2), pancreatic (1), ovarian (1), malignant-mesothelioma (1) head and neck (1) hepatocellular carcinoma (1) and sarcoma (1). The patients, whose blood or marrow contained tumorigenic CTCs, developed metastasis. Interestingly, there was a correlation between sites of CTC-derived tumors in the mice and sites of metastatic spread in the patients. CTC-derived tumors were successfully transferred to subsequent PDX mice, enabling the establishment of large treatment groups to study drug reactivity of these tumors. Summary: This study describes a functional assay to characterize the CTCs subtypes with a high metastatic potential, which utilizes the capacity of CTCs to form tumors in a permissive immune-free environment. CTC-derived tumors may offer a new tool to predict the significance of these malignant cells and prevent metastatic spread. Citation Format: Netta R. Shraga, Amihai Lieberman, Neta Moskovits, Alejandro Livoff, Evgeny Solomonov, Inbar Ben Shachar, Aron Popovtzer, Salomon M. Stemmer*, Izhak Haviv*. Circulating tumor cells from patients' blood induce tumors in a personalized xenograft mouse model: A functional approach to assess the patients' premetastatic disease state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1030.
Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor's microenvironment, may therefore potentiate immune attack on the tumor. NT-219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT-219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT-219 efficacy was demonstrated in Patient-Derived tumor Xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head & neck, when added-on to the approved therapies. In these models, NT-219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, Oxaliplatin). We recently demonstrated that NT-219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT-219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of Cetuximab. The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs. Citation Format: Lana Kuperschmidt, Hadas Reuveni, Shani Carmi, Neta Moskovits, Netta R. Shraga, Evgeny Solomonov, Ohad Ronen, Salomon Stemmer, Izhak Haviv. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2754.
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