Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors

  • Cell. 2021 Sep 16;184(19):4996-5014.e26. doi: 10.1016/j.cell.2021.08.020.
Megan L Burger  1 ,  Amanda M Cruz  2 ,  Grace E Crossland  1 ,  Giorgio Gaglia  3 ,  Cecily C Ritch  3 ,  Sarah E Blatt  1 ,  Arjun Bhutkar  1 ,  David Canner  2 ,  Tamina Kienka  1 ,  Sara Z Tavana  1 ,  Alexia L Barandiaran  1 ,  Andrea Garmilla  1 ,  Jason M Schenkel  4 ,  Michelle Hillman  1 ,  Izumi de Los Rios Kobara  1 ,  Amy Li  2 ,  Alex M Jaeger  1 ,  William L Hwang  5 ,  Peter M K Westcott  1 ,  Michael P Manos  6 ,  Marta M Holovatska  6 ,  F Stephen Hodi  7 ,  Aviv Regev  8 ,  Sandro Santagata  9 ,  Tyler Jacks  10
Affiliations
  • 1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 2. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 4. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 5. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 6. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • 7. Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • 8. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
  • 9. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
  • 10. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 34534464 DOI: 10.1016/j.cell.2021.08.020
Abstract

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and Sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Keywords
CCR6; CD8 T cell; TCF1; Tc17; checkpoint blockade; immunodominance; lung cancer; neoantigen; vaccine.