Biology subjects

Amoozgar, Z.

Publications and source records attributed to Amoozgar, Z..

3 recordsLinked to original sources

bioRxiv2023

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, and in vivo T-cell depletion and CD8+ T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-{gamma}+ T-cells. Depletion of CD8+ but not CD4+ T-cells compromised efficacy. Conversely, CD8+ T-cell transfer from Cxcr3-/- versus Cxcr3+/+ mice into Rag1-/- immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 "priming") with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients. One Sentence SummaryImmune microenvironment reprogramming by chemotherapy and priming using CTLA-4 blockade render ICCs responsive to anti-PD-1 immunotherapy.

cancer biology↗

bioRxiv2022

Breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation

Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross-species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-{gamma} and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor-draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.

cancer biology↗

bioRxiv2022

Combined blockade of VEGF, Angiopoietin-2, and PD1 reprograms glioblastoma endothelial cells into quasi-antigen-presenting cells

Glioblastoma (GBM) remains a highly aggressive and uniformly fatal tumor, with a 5-year survival of <10%. Moreover, all randomized clinical trials with immune-checkpoint blockers have failed to date. Here we report that tumor endothelial cell (EC) dysfunction confers resistance to immunotherapy in preclinical GBM models. Anti-VEGF-therapy-induced vascular normalization is insufficient to fully restore the EC function and alleviate inflammatory edema induced by blocking programmed cell death protein 1 (PD1). Strikingly, concomitant blockade of angiopoietin 2 (Ang2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD1) reprograms dysfunctional ECs to quasi-antigen presenting cells and upregulates receptors required for cytotoxic T lymphocyte entry into the tumor. Blocking VEGF, Ang2, and PD1 induces durable anti-tumor response while controlling edema. Upregulation of the transcription factor T-bet is necessary for generating resident memory T cells elicited by this combination therapy. Moreover, a human GBM organoid model formed from human cancer cells, ECs, CD14 and CD8 cells recapitulated these findings. Our study reveals the role of Ang2 in resistance to VEGF and/or PD1-blockade and provides a compelling rationale for clinical evaluation of this combination in GBM patients.

cancer biology↗