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

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. ManosMarta M. Holovatska, F. Stephen Hodi, Aviv Regev, Sandro Santagata, Tyler Jacks

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4996-5014.e26
Journal	Cell
Volume	184
Issue number	19
DOIs	https://doi.org/10.1016/j.cell.2021.08.020
State	Published - Sep 16 2021
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2021.08.020

Cite this

Burger, M. L., Cruz, A. M., Crossland, G. E., Gaglia, G., Ritch, C. C., Blatt, S. E., Bhutkar, A., Canner, D., Kienka, T., Tavana, S. Z., Barandiaran, A. L., Garmilla, A., Schenkel, J. M., Hillman, M., de los Rios Kobara, I., Li, A., Jaeger, A. M., Hwang, W. L., Westcott, P. M. K., ... Jacks, T. (2021). Antigen dominance hierarchies shape TCF1⁺ progenitor CD8 T cell phenotypes in tumors. Cell, 184(19), 4996-5014.e26. https://doi.org/10.1016/j.cell.2021.08.020

Burger, ML, Cruz, AM, Crossland, GE, Gaglia, G, Ritch, CC, Blatt, SE, Bhutkar, A, Canner, D, Kienka, T, Tavana, SZ, Barandiaran, AL, Garmilla, A, Schenkel, JM, Hillman, M, de los Rios Kobara, I, Li, A, Jaeger, AM, Hwang, WL, Westcott, PMK, Manos, MP, Holovatska, MM, Hodi, FS, Regev, A, Santagata, S & Jacks, T 2021, 'Antigen dominance hierarchies shape TCF1⁺ progenitor CD8 T cell phenotypes in tumors', Cell, vol. 184, no. 19, pp. 4996-5014.e26. https://doi.org/10.1016/j.cell.2021.08.020

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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",

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AU - Burger, Megan L.

AU - Cruz, Amanda M.

AU - Crossland, Grace E.

AU - Gaglia, Giorgio

AU - Ritch, Cecily C.

AU - Blatt, Sarah E.

AU - Bhutkar, Arjun

AU - Canner, David

AU - Kienka, Tamina

AU - Tavana, Sara Z.

AU - Barandiaran, Alexia L.

AU - Garmilla, Andrea

AU - Schenkel, Jason M.

AU - Hillman, Michelle

AU - de los Rios Kobara, Izumi

AU - Li, Amy

AU - Jaeger, Alex M.

AU - Hwang, William L.

AU - Westcott, Peter M.K.

AU - Manos, Michael P.

AU - Holovatska, Marta M.

AU - Hodi, F. Stephen

AU - Regev, Aviv

AU - Santagata, Sandro

AU - Jacks, Tyler

PY - 2021/9/16

Y1 - 2021/9/16

N2 - 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.

AB - 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.

KW - CCR6

KW - CD8 T cell

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