Biology subjects

Izadmehr, S.

Publications and source records attributed to Izadmehr, S..

3 recordsLinked to original sources

bioRxiv2024

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

BackgroundBacillus Calmette-Guerin (BCG) is the standard of care treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet many patients develop recurrent disease despite evidence of ongoing immune activation. We investigated mechanisms of immune escape in BCG-unresponsive tumors and evaluated the therapeutic potential of targeting the HLA-E/NKG2A axis. MethodsSingle-cell RNA sequencing, spatial immunophenotyping, proteomic profiling, and functional ex vivo assays were performed using tumors and urine samples from patients with BCG-naive and BCG-unresponsive NMIBC. ResultsBCG-unresponsive tumors were enriched for HLA-E-expressing malignant cells compared with BCG-naive tumors. Increased HLA-E expression was associated with enhanced IFN-{gamma} signaling and was induced by IFN-{gamma} stimulation in primary tumor cells and bladder cancer tumor lines. Spatial analyses demonstrated accumulation of NKG2A+ NK and CD8 T cells in proximity to HLA-Ehigh tumor cells, with increased NKG2A:HLA-E interactions in BCG-unresponsive tumors. Despite high expression of cytotoxic mediators, NKG2A+ effector cells displayed impaired degranulation. Blockade of NKG2A with monalizumab restored degranulation of and cytotoxicity by tumor-infiltrating lymphocytes in autologous tumor co-cultures. ConclusionsBCG-unresponsive NMIBC tumors are enriched for HLA-E-expressing tumor cells and NKG2A+ effector lymphocytes, with increased engagement of the HLA-E/NKG2A axis within the tumor microenvironment. These findings identify the HLA-E/NKG2A axis as a therapeutic vulnerability and provide a rationale for clinical evaluation of NKG2A blockade as a bladder-sparing strategy for patients with BCG-unresponsive disease.

cancer biology↗

bioRxiv2024

Cooperativity of c-MYC with Krüppel-Like Factor 6 Splice Variant 1 induces phenotypic plasticity and promotes prostate cancer progression and metastasis

Metastasis remains a major cause of morbidity and mortality in men with prostate cancer, and the functional impact of the genetic alterations, alone or in combination, driving metastatic disease remains incompletely understood. The proto-oncogene c-MYC, commonly deregulated in prostate cancer. Transgenic expression of c-MYC is sufficient to drive the progression to prostatic intraepithelial neoplasia and ultimately to moderately differentiated localized primary tumors, however, c-MYC-driven tumors are unable to progress through the metastatic cascade, suggesting that a "second-hit" is necessary in the milieu of aberrant c-MYC-driven signaling. Here, we identified cooperativity between c-MYC and KLF6-SV1, an oncogenic splice variant of the KLF6 gene. Transgenic mice that co-expressed KLF6-SV1 and c-MYC developed progressive and metastatic prostate cancer with a histological and molecular phenotype like human prostate cancer. Silencing c-MYC expression significantly reduced tumor burden in these mice supporting the necessity for c-MYC in tumor maintenance. Unbiased global proteomic analysis of tumors from these mice revealed significantly enriched vimentin, a dedifferentiation and pro-metastatic marker, induced by KLF6-SV1. c-MYC-positive tumors were also significantly enriched for KLF6-SV1 in human prostate cancer specimens. Our findings provide evidence that KLF6-SV1 is an enhancer of c-MYC-driven prostate cancer progression and metastasis, and a correlated genetic event in human prostate cancer with potential translational significance.

cancer biology↗

bioRxiv2020

Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing

Adaptive immunity and tumor-promoting inflammation exist in delicate balance in individual tumor microenvironments; however, the role of this balance in defining sensitivity and resistance to PD-1/PD-L1 blockade therapy in urothelial cancer and other malignancies is poorly understood. We pursued an unbiased systems biology approach using bulk RNA sequencing data to examine pre-treatment molecular features associated with sensitivity to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer and identified an adaptive_immune_response module associated with response and an inflammatory_response module and stromal module associated with resistance. We mapped these gene modules onto single-cell RNA sequencing data demonstrating the adaptive_immune_response module emanated predominantly from T, NK, and B cells, the inflammatory_response module from monocytes/macrophages, and the stromal module from fibroblasts. The adaptive_immune_response:inflammatory_response module expression ratio in individual tumors, reflecting the balance between antitumor immunity and tumor-associated inflammation and coined the 2IR score, best correlated with clinical outcomes and was validated in an independent cohort. Individual monocytes/macrophages with low 2IR scores demonstrated upregulation of proinflammatory genes including IL1B and downregulation of antigen presentation genes, were unrelated to classical M1 versus M2 polarization, and were enriched in pre-treatment peripheral blood from patients with PD-L1 blockade-resistant metastatic urothelial cancer. Single sentence summaryProinflammatory monocytes/macrophages, present in tumor and blood, are associated with resistance to immune checkpoint blockade in urothelial cancer.

genomics↗