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Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors

89 Pages Posted: 20 Jan 2021 Publication Status: Published

See all articles by Megan Burger

Megan Burger

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Amanda M. Cruz

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Grace E. Crossland

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Giorgio Gaglia

Harvard Medical School - Department of Pathology

Cecily C. Ritch

Harvard Medical School - Department of Pathology

Sarah E. Blatt

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Arjun Bhutkar

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

David Canner

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology

Tamina Kienka

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Sara Tavana

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Andrea Garmilla

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Jason Schenkel

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Michelle Hillman

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Izumi de los Rios Kobara

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Amy Li

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Harvard Medical School

William Hwang

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Peter Westcott

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Aviv Regev

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Masssachusetts Institute of Technology and Harvard University - Broad Institute; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)

Sandro Santagata

Harvard Medical School - Department of Pathology

Tyler E. Jacks

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)

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Abstract

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about their interplay and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we find 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 are enriched for a TCF1+ progenitor phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response does not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ progenitor cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets indicates CCR6+ TCF1+ cells exist across human cancers and correlate with poor ICB response. Vaccination eliminates CCR6+ TCF1+ cells and dramatically expands the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

Keywords: TCF1; neoantigen; immunodominance; CCR6; Tc17; vaccine; lung cancer

Suggested Citation

Burger, Megan and Cruz, Amanda M. and Crossland, Grace E. and Gaglia, Giorgio and Ritch, Cecily C. and Blatt, Sarah E. and Bhutkar, Arjun and Canner, David and Kienka, Tamina and Tavana, Sara and Garmilla, Andrea and Schenkel, Jason and Hillman, Michelle and de los Rios Kobara, Izumi and Li, Amy and Hwang, William and Westcott, Peter and Regev, Aviv and Santagata, Sandro and Jacks, Tyler E., Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors. Available at SSRN: https://ssrn.com/abstract=3770111 or http://dx.doi.org/10.2139/ssrn.3770111
This version of the paper has not been formally peer reviewed.

Megan Burger

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Amanda M. Cruz

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Grace E. Crossland

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Giorgio Gaglia

Harvard Medical School - Department of Pathology ( email )

75 Francis St.
Boston, MA 02115
United States

Cecily C. Ritch

Harvard Medical School - Department of Pathology ( email )

75 Francis St.
Boston, MA 02115
United States

Sarah E. Blatt

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Arjun Bhutkar

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

David Canner

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Tamina Kienka

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Sara Tavana

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Andrea Garmilla

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Jason Schenkel

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Michelle Hillman

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Izumi De los Rios Kobara

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Amy Li

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

William Hwang

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Peter Westcott

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Aviv Regev

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology ( email )

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Masssachusetts Institute of Technology and Harvard University - Broad Institute ( email )

415 Main Street
Cambridge, MA 02142
United States

Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI) ( email )

31 Ames St, 68-171
Cambridge, MA
United States

Sandro Santagata

Harvard Medical School - Department of Pathology ( email )

75 Francis St.
Boston, MA 02115
United States

Tyler E. Jacks (Contact Author)

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology ( email )

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI) ( email )

31 Ames St, 68-171
Cambridge, MA
United States

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