Biology subjects

Shukla, S. A.

Publications and source records attributed to Shukla, S. A..

3 recordsLinked to original sources

bioRxiv2020

Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1-3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

cancer biology↗

bioRxiv2020

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to graft-versus-leukemia

Resistance to the graft-versus-leukemia (GvL) effect remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis of GvL resistance for advanced lymphoid malignancies remains incompletely understood. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features shape GvL outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post- HSCT relapse are shaped by distinct molecular dynamics and suggest that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for HLA loss was observed, even when present in pre-transplant subpopulations. Regardless of post-transplant relapse kinetics, gain of stem cell modules was a common signature associated with leukemia relapse. These data elucidate the biological pathways that underlie GvL resistance and post-transplant relapse. One Sentence SummaryWe find that the clinical kinetics of chronic lymphocytic leukemia relapse after stem cell transplant are underwritten by distinct genetic and epigenetic evolutionary trajectories and suggest that the selection pressures of the post-transplant, immunologic bottleneck are unlike those imposed by chemotherapy.

cancer biology↗

bioRxiv2020

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer

Tumor epitopes - peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.

cancer biology↗