Public Resources


Discovering Dominant Tumor Immune Archetypes in a Pan-Cancer Census

Alexis J. Combes , Bushra Samad , Jessica Tui , Nayvin W. Chew , Peter Yan , Gabriella C. Reeder , Divyashree Kushnoor , Alan Shen , Brittany Davidson, , Austin Edwards , Mohammad Nasser ,Kevin C. Barry  Tristan Courau , Taymour Hammoudi , Rafael J Arguëllo  Arjun Arkal Rao , Adam B. Olshen    The Immunoprofiler consortium, Cathy Cai , Jenny Zhan , Katelyn C. Davis , Robin K. Kelley  Jocelyn S. Chapman   Chloe Attreya   , Amar Patel   , Adil I. Daud   Patrick Ha   Aaron A. Diaz   Johannes Kratz    Eric A. Collisson   , Gabriela K Fragiadakis ,   David Erle ,   Alexandre Boissonnas   Saurabh Asthana   Vincent Chan  Matthew F. Krummel


Cancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system—here ‘Archetypes’—creating prototypical non-destructive tumor immune microenvironments (TME) and modulating tumor-targeting. To discover the dominant immune system archetypes the UCSF Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.


Global absence and targeting of protective immune states in severe COVID-19

Alexis J. Combes  Tristan Courau    Nicholas F. Kuhn   Kenneth H. Hu   Arja Ray   William S. Chen   Nayvin W. Chew  Simon J. Cleary   Divyashree Kushnoor  Gabriella C. Reeder  Alan Shen  Jessica Tsui  Kamir J. Hiam-Galvez  Priscila Muñoz-Sandoval  Wandi S. Zhu  David S. Lee  Yang Sun   Ran You Mélia Magnen   Lauren Rodriguez  K. W. Im  Nina K. Serwas Aleksandra Leligdowicz Colin R. Zamecnik   Rita P. Loudermilk   Michael R. Wilson   Chun J. Ye Gabriela K. Fragiadakis  Mark R. Looney   Vincent Chan Alyssa Ward   Sidney Carrillo The UCSF COMET Consortium*  Michael Matthay David J. Erle  Prescott G. Woodruff   Charles Langelier    Kirsten Kangelaris    Carolyn M. Hendrickson Carolyn Calfee Arjun Arkal Rao Matthew F. Krummel


To gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood—including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence



A Natural Killer/Dendritic Cell Axis Defines Responsive Tumor Microenvironments in Melanoma

Kevin C. Barry, Joy Hsu, Miranda L. Broz, Francisco J. Cueto,Mikhail Binnewies, Alexis J. Combes,Amanda E. Nelson, Kimberly Loo,Raj Kumar, Michael D. Rosenblum, Michael D. Alvarado, Denise M. Wolf, Dusan Bogunovic, Nina Bhardwaj, Adil I. Daud, Patrick K. Ha, William R. Ryan,Joshua L. Pollack, Bushra Samad, Saurabh Asthana, Vincent Chan, Matthew F. Krummel


Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in the tumor through production of Flt3L. Although anti-PD-1 “checkpoint” immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis for novel therapies.