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

Megan L Burger; Amanda M Cruz; Grace E Crossland; Giorgio Gaglia; Cecily C Ritch; Sarah E Blatt; Arjun Bhutkar; David Canner; Tamina Kienka; Sara Z Tavana; Alexia L Barandiaran; Andrea Garmilla; Jason M Schenkel; Michelle Hillman; Izumi de Los Rios Kobara; Amy Li; Alex M Jaeger; William L Hwang; Peter M K Westcott; Michael P Manos; Marta M Holovatska; F Stephen Hodi; Aviv Regev; Sandro Santagata; Tyler Jacks

doi:10.1016/j.cell.2021.08.020

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.

Authors

Megan L Burger¹, Amanda M Cruz², Grace E Crossland¹, Giorgio Gaglia³, Cecily C Ritch³, Sarah E Blatt¹, Arjun Bhutkar¹, David Canner², Tamina Kienka¹, Sara Z Tavana¹, Alexia L Barandiaran¹, Andrea Garmilla¹, Jason M Schenkel⁴, Michelle Hillman¹, Izumi de Los Rios Kobara¹, Amy Li², Alex M Jaeger¹, William L Hwang⁵, Peter M K Westcott¹, Michael P Manos⁶, Marta M Holovatska⁶, F Stephen Hodi⁷, Aviv Regev⁸, Sandro Santagata⁹, Tyler Jacks¹⁰

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung / immunology*
Amino Acid Sequence
Animals
Antigens, Neoplasm / immunology*
CD8-Positive T-Lymphocytes / immunology*
CTLA-4 Antigen / metabolism
Epitopes
Female
Hepatocyte Nuclear Factor 1-alpha / metabolism*
Humans
Immune Checkpoint Inhibitors / pharmacology
Lung Neoplasms / immunology*
Lung Neoplasms / pathology
Mice
Peptides / chemistry
Phenotype
Programmed Cell Death 1 Receptor / metabolism
RNA-Seq
Receptors, Antigen, T-Cell / metabolism
Receptors, CCR6 / metabolism
Single-Cell Analysis
Stem Cells / immunology*
Vaccination

Substances

Antigens, Neoplasm
CCR6 protein, mouse
CTLA-4 Antigen
Epitopes
Hepatocyte Nuclear Factor 1-alpha
Hnf1a protein, mouse
Immune Checkpoint Inhibitors
Pdcd1 protein, mouse
Peptides
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell
Receptors, CCR6

Abstract

Publication types

MeSH terms

Substances

Grants and funding