Melanoma
Shravan Leonard-Murali, MD
Resident Physician/Postdoctoral Research Fellow
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
Department of Surgery, Allegheny Health Network, Pittsburgh, PA, USA
Pittsburgh, Pennsylvania, United States
Shravan Leonard-Murali, MD
Resident Physician/Postdoctoral Research Fellow
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
Department of Surgery, Allegheny Health Network, Pittsburgh, PA, USA
Pittsburgh, Pennsylvania, United States
Shravan Leonard-Murali, MD
Resident Physician/Postdoctoral Research Fellow
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
Department of Surgery, Allegheny Health Network, Pittsburgh, PA, USA
Pittsburgh, Pennsylvania, United States
Chetana Bhaskarla, PhD
Postdoctoral Researcher
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Ghanshyam Yadav, PhD
Postdoctoral Researcher
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Sudeep Maurya, PhD
Postdoctoral Researcher
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Chenna Galiveti, PhD
Postdoctoral Researcher
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Joshua Tobin, BS
Laboratory Manager
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Rachel Kann, BS
Medical Student
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Eishan Ashwat, BS
Medical Student
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Patrick Murphy, PhD
Research Assistant Professor
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Anish Chakka, PhD
Bioinformatics Analyst
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA., United States
Vishal Soman, BS
Bioinformatics Analyst
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA., United States
Paul Cantalupo, PhD
Bioinformatics Analyst
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA., United States
Xinming Zhuo, PhD
Bioinformatics Analyst
UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Gopi Vyas, MS
Bioinformatics Analyst
UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Dara Kozak, BS
Director of Laboratory Services
UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Lindsey Kelly, PhD
Laboratory Manager
UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Ed Smith, MBA
Director of Clinical Genomics Services
UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Uma Chandran, PhD
Research Associate Professor
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA., United States
Yen-Michael Hsu, MD, PhD
Director
UPMC Immunologic Monitoring and Cellular Products Laboratory, University of Pittsburgh, Pittsburgh, PA, USA., United States
Udai Kammula, MD
Director
Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA., United States
Immune checkpoint inhibition (ICI) has shown significant efficacy in select metastatic cancers with high tumor mutational burden (TMB). However, most solid cancers have low TMB and are ICI-resistant. We hypothesized that immunogenomics of metastatic uveal melanoma (UM), a prototypic ICI-resistant cancer, would provide insights toward developing therapies for immune-resistant cancers.
Methods:
Freshly resected UM metastases (n=100) were procured from patients (n=84) enrolled in NCT01814046 and NCT03467516. No patients had responses to ICI. Metastases were profiled with whole genome sequencing, total RNAseq, TCR repertoire analyses, single-cell RNAseq, and ex vivo tumor-infiltrating lymphocyte (TIL) culture expansion and anti-tumor reactivity testing.
Results:
Unbiased correlative principal component analysis of total RNAseq segregated metastases by canonical hallmark immune pathways, including allograft rejection, interferon gamma response, and interferon alpha response. Single-cell RNAseq revealed T cell-inflamed microenvironments in inflamed vs noninflamed metastases, as evidenced by increased exhausted CD8 T cells (ratio=40.73, P< 0.001) and antigen presenting cell function. Tumor cells from noninflamed metastases upregulated CTNNB1 (beta-catenin) which has been linked to tumor immune resistance. As validation, transcriptomic inflammation predicted ex vivo expansion of tumor reactive TIL (rho=+0.47, P< 0.001; AUC=0.85, P< 0.001). Interestingly, transcriptomic inflammation correlated with TCR diversity (rho=+0.54, P< 0.001) but not clonality (rho=+0.02, P=ns). Ex vivo culture rescued TIL cell count and clonality (P=0.004). Finally, when retrospectively applied to NCT01814046, transcriptomic inflammation predicted magnitude of tumor regression (rho=-0.68, P=0.001) and survival after TIL adoptive transfer (PFS: HR=0.36, P=0.044; OS: HR=0.24, P</em>=0.009).
Conclusions:
We demonstrate that transcriptomic inflammation predicts anti-tumor reactivity and clinical efficacy of TIL adoptively transferred into patients with metastatic UM. We are adapting tumor biopsy transcriptomics into a TIL biomarker for UM and other immune-resistant cancers.