Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Jinyang Li, Katelyn T. Byrne, Fangxue Yan, Taiji Yamazoe, Zeyu Chen, Timour Baslan, Lee P. Richman, Jeffrey H. Lin, Yu H. Sun, Andrew J. Rech, David Balli, Ceire A. Hay, Yogev Sela, Allyson J. Merrell, Shannon M. Liudahl, Naomi Gordon, Robert J. Norgard, Salina Yuan, Sixiang Yu, Timothy Chao & 9 others Shuai Ye, T. S.Karin Eisinger-Mathason, Robert B. Faryabi, John W. Tobias, Scott W. Lowe, Lisa Coussens, E. John Wherry, Robert H. Vonderheide, Ben Z. Stanger

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy. Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.

Original languageEnglish (US)
JournalImmunity
DOIs
StateAccepted/In press - Jan 1 2018

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Intrinsic Factor
Immunotherapy
Neoplasms
Clone Cells
Tumor Microenvironment
T-Lymphocytes
Libraries
Chemokine CXCL1
Cellular Microenvironment
Pancreatic Neoplasms
Epigenomics
Adenocarcinoma
Phenotype

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Li, J., Byrne, K. T., Yan, F., Yamazoe, T., Chen, Z., Baslan, T., ... Stanger, B. Z. (Accepted/In press). Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity. https://doi.org/10.1016/j.immuni.2018.06.006

Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. / Li, Jinyang; Byrne, Katelyn T.; Yan, Fangxue; Yamazoe, Taiji; Chen, Zeyu; Baslan, Timour; Richman, Lee P.; Lin, Jeffrey H.; Sun, Yu H.; Rech, Andrew J.; Balli, David; Hay, Ceire A.; Sela, Yogev; Merrell, Allyson J.; Liudahl, Shannon M.; Gordon, Naomi; Norgard, Robert J.; Yuan, Salina; Yu, Sixiang; Chao, Timothy; Ye, Shuai; Eisinger-Mathason, T. S.Karin; Faryabi, Robert B.; Tobias, John W.; Lowe, Scott W.; Coussens, Lisa; Wherry, E. John; Vonderheide, Robert H.; Stanger, Ben Z.

In: Immunity, 01.01.2018.

Research output: Contribution to journalArticle

Li, J, Byrne, KT, Yan, F, Yamazoe, T, Chen, Z, Baslan, T, Richman, LP, Lin, JH, Sun, YH, Rech, AJ, Balli, D, Hay, CA, Sela, Y, Merrell, AJ, Liudahl, SM, Gordon, N, Norgard, RJ, Yuan, S, Yu, S, Chao, T, Ye, S, Eisinger-Mathason, TSK, Faryabi, RB, Tobias, JW, Lowe, SW, Coussens, L, Wherry, EJ, Vonderheide, RH & Stanger, BZ 2018, 'Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy', Immunity. https://doi.org/10.1016/j.immuni.2018.06.006
Li, Jinyang ; Byrne, Katelyn T. ; Yan, Fangxue ; Yamazoe, Taiji ; Chen, Zeyu ; Baslan, Timour ; Richman, Lee P. ; Lin, Jeffrey H. ; Sun, Yu H. ; Rech, Andrew J. ; Balli, David ; Hay, Ceire A. ; Sela, Yogev ; Merrell, Allyson J. ; Liudahl, Shannon M. ; Gordon, Naomi ; Norgard, Robert J. ; Yuan, Salina ; Yu, Sixiang ; Chao, Timothy ; Ye, Shuai ; Eisinger-Mathason, T. S.Karin ; Faryabi, Robert B. ; Tobias, John W. ; Lowe, Scott W. ; Coussens, Lisa ; Wherry, E. John ; Vonderheide, Robert H. ; Stanger, Ben Z. / Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. In: Immunity. 2018.
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abstract = "The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy. Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.",
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AU - Yan, Fangxue

AU - Yamazoe, Taiji

AU - Chen, Zeyu

AU - Baslan, Timour

AU - Richman, Lee P.

AU - Lin, Jeffrey H.

AU - Sun, Yu H.

AU - Rech, Andrew J.

AU - Balli, David

AU - Hay, Ceire A.

AU - Sela, Yogev

AU - Merrell, Allyson J.

AU - Liudahl, Shannon M.

AU - Gordon, Naomi

AU - Norgard, Robert J.

AU - Yuan, Salina

AU - Yu, Sixiang

AU - Chao, Timothy

AU - Ye, Shuai

AU - Eisinger-Mathason, T. S.Karin

AU - Faryabi, Robert B.

AU - Tobias, John W.

AU - Lowe, Scott W.

AU - Coussens, Lisa

AU - Wherry, E. John

AU - Vonderheide, Robert H.

AU - Stanger, Ben Z.

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N2 - The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy. Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.

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